Process for making amino-alkyl-para amino-ortho substituted-benzoic acid esters and amides



United States Patent PROCESS FOR MAKING AMINO-ALKYL-PARA AMINO-ORTHGSUBSTilTUTED-BENZOIC ACID ESTERS ANT) AMTDES Merrill E. Specter,Kalamazoo Township, Kalamazoo County, Mich., assignor to The UpjohnCompany, Kalamazoo, Mich, a corporation of Michigan No Drawing. FiledMay 24, 1954, Ser. No. 432,033

2 Claims. (Cl. 260247.1)

This invention rel-ates to a process for preparing benzoic acidderivatives and to novel products thereof. More particularly, theinvention relates to a process for preparing hindered 4-aminobenzoicacid derivatives and to novel hindered 4-aminobenzoic acid derivativesso produced.

Esters of 4-aminobenzoic acid are known to have valuable therapeuticproperties, especially as local anesthetics. Thus, B-diethylaminoethyl4-aminobenzoate, commonly known as procaine, is particularly useful as alocal anesthetic. These esters, however, have the disadvantage of beingrelatively easily hydrolyzed. It has been found that this disadvantageis largely avoided if the carboxylate group is hindered, i.e., if atleast one of the carbon atoms ortho to the carboxylate group in the1-position bears a substituent such as R or R as set forth in greaterdetail hereinafter. Thus, 2,6-dimethylprocaine, for example, is morestable to hydrolysis than procaine. This and other hindered4-aminobenzoic acid derivatives, however, cannot be prepared by themethods known for the preparation of procaine.

Furthermore, by the novel procedure of the invention, new andtherapeutically useful hindered 4-aminobenzoic acid derivatives whichwere unavailable hitherto are prepared.

It is an object of the invention, therefore, to provide a new processfor the preparation of hindered 4-aminobenzoic acid derivatives. Anotherobject of the invention is to provide new and novel hindered4-aminobenzoic acid derivatives. Other objects and features of theinven- .tion will be apparent to those skilled in the art to which thisinvention pertains.

These objects are accomplished in the present invention by subjecting ahindered 4-oxo-2-cyclohexene-1- carboxylic acid ester to oximation;aromatizing and acylating the resulting hindered4-oximino-2-cyclohexene-1- carboxylic acid ester; hydrolyzing theresulting hindered 4-acylamidobenzoic acid ester followed by acylationto obtain a hindered 4-acylarnidobenzoic acid; reacting the hindered4-acylamidobenzoic acid with an inorganic acid halide to obtain ahindered 4-acylamidobenzoyl halide, reacting the hindered4-acylamidobenzoyl halide with a compound of the formula:

HY CnH nR wherein Y is a member selected from the group consisting ofoxygen, sulfur, imino, and lower-alkylimino, R is a secondary-aminoradical, and n is an integer from one to six inclusive, to obtain ahindered 4-acylamidobenzoic acid compound; and hydrolyzing said compoundto form the corresponding hindered 4-aminobenzoic acid compound.

The term secondary-amino radical" as used in the specification andclaims refers to a radical obtained by removing the hydrogen atomattached to the nitrogen atom of a secondary amine.

In accordance with a specific embodiment of the process of theinvention, a hindered 4-oxo-2-cyclohexene-lcarboxylic acid ester isconverted to its oxime by any suitable procedure. Ordinarily, this isconveniently accomplished by reacting the 4-oxo group with ahydroxylamine salt such as hyroxylamine hydrochloride, hydroxylaminesulfate, and the like, in a suitable solvent such as a pyridine-alcoholsolution, to form the corresponding hindered4-oximin0-2-cyclohexene-l-carboxylic acid ester. Solvents other thanpyridine can be used in the reaction such as, for example, a lower-alkylpyridine, quinoline, isoquinoline, and the like. The conversion of thehindered 4-oxo-2-cyclohexene-l-carboxylic acid ester to thecorresponding hindered 4-oximino-2-cyclohexene-l-carboxylic acid estermay likewise be effected by reacting the ketone with a hydroxylarninesalt in alcohol in the presence of an acid-binding agent such as sodiumacetate, potassium acetate, lithium propionate, and the like. 1

The hindered 4-oximino-2-cyclohexene 1 carboxylic acid ester is thenaromatized and acylated to form the corresponding hindered4-acylamidobenzoic acid ester. This is preferably accomplished in anacidic medium containing an anhydride of a lower-aliphatic acid such asacetic, propionic, butyric, and isobutyric anhydride, and the like; ahydrogen halide such as hydrogen chloride or hydrogen bromide; and alower-aliphatic acid such as acetic acid, propionic acid, butyric acid,isobutyric acid, and the like. In this reaction, it is ordinarilypreferable to use an acid together with its anhydride. For example, ifacetic anhydride is used, acetic acid is preferred and likewise, ifpropionic anhydride is used, propionic acid is preferred. Whilearomatization and acylation of the hindered4-oxirnino-2-cyclohexene-l-carboxylic acid ester can be effected in theabsence of a lower-aliphatic acid, superior results are obtained when alower-aliphatic acid is present in the reaction mixture. Further,although concentration of the acylating agent may be varied, at least anequimolar amount of the acylatin-g agent with respect to the startingmaterial is employed and preferably, a molar ratio between about 3:1 andabout 8:1. At least one mole of the lower-aliphatic acid must be presentto secure optimum results. Still further, highly satisfactory resultsare obtained when the reaction mixture is substantially saturated withthe hydrogen halide. It is ordinarily preferred to maintain thetemperature of the reaction between about degrees and about degreescentigrade although temperatures between about sixty degrees centigradeand about 200 degrees centigrade can also be utilized. The reactionmixture is heated for a period of at least one hour. Upon completion ofthe reaction, the mixture is worked up by any convenient procedure.Advantageously, the reaction mixture is added to ice or water, and thehindered 4- acylamidobenzoic acid ester is recovered and recrystallizedfrom a suitable solvent.

Alternatively, aromatization and acylation can likewise be effected byreacting a pyridine solution of the starting hindered4-oximino-2-cyclohexene-l-carboxylic acid ester with a solutioncontaining an equimolar quantity of a lower-aliphatic acid halidedissolved in a lower-aliphatic acid anhydride, at a temperature betweenabout fifty degrees and about 100 degrees centigrade. When the reactionmoderates, the mixture is refiuxed for at least one hour. After reflux,the mixture is poured into water or ice and worked up, for example, bythe aforedescribed convention-a1 procedure, to obtain the desired4-acylamidobenzoic acid ester.

The hindered 4-acylamidobenzoic acid ester is hydrolyzed, i.e.,deacylated and de-esterified, and then acylated. This ordinarilyinvolves hydrolysis of both the ester function and the 4-acylamidogroup, followed by acylation of the resulting 4-amino group toreconstitute the 4-acylamido group. The acyl group in the resulting4-acylamidobenzoic acid, therefore, may or may not be the same as thatof the starting hindered 4-acylamidobenzoic acid ester. It has beenfound advantageous to effect the hydrolysis by heating the4-acylamidobemoic acid ester at a temperature between about 125 degreesand about 200 degrees centigrade, in a mixture containing an alkali suchas potassium hydroxide, sodium hydroxide, and the like, and a glycolsuch as ethylene glycol, propylene glycol, and the like; and to effectac'ylation of the hydrolyzed compound in the presence of water, atatemperature between about Zero degrees centigrade and about 75 degreescentigrade, by reaction with an acylating agent such as ananhydride of alower-aliphatic acid, e.g., acetic anhydride, propionic anhydride,butyric anhydride and the like; an arylsultonyl halide such as tosylchloride, tosyl bromide, benzenesulfonyl chloride, and the like; or anaroyl halide such as benzoyl chloride, benzoyl bromide, and the like. Inthe hydrolysis reaction, between about three and about ten moles ofalkali per mole of starting 4-ac ylamidobenzoic acid ester arepreferred, although satisfactory results are likewise obtained by theuse of larger amounts of alkali such as up to about fifteen or evenabout twenty moles of alkali per mole of starting 4-acylamidobenzoicacid ester. The reaction temperature should not substantially exceed 200de'grees centigrade to prevent decarboxylation of the hindered4-acylamidobenzoic acid product. In the acylation reaction, at least onemole of acylating a ent per mole of ester is used, although ordinarily,an excess will be used such as from about five to about ten moles ofacylating agent per rnole of ester. The acylating agent can bepreseut'in themixturein equimolar amounts with the alkali material used.Upon completion of the reaction, the mixture is worked up by anyconvenient procedure. Advantageously, amineral acid is added, thehindered 4-acylamidobenzoicacid is extracted with a suitable solvent,e;g., ether, the solvent is evaporated, the "residue is extracted withcaustic solution to obtain a water solution of a salt of t'lieor'ganicacid, and this solution is acidified to precipitate the free organicacid. Thelatter can be further purified ifso desired, such as byrecrystallization from a suitable solvent.

Deacylation of the hindered 4 -acylamidobenzoic acid ester can likewisebe'accomplishe'd in other ways such as by'reac'tion with a dilute alkalifor a short period of time, i1e.,.about four hours, or by alcoholysi's,or 'ammonolysis, the alcoholysis' and ammonolysis reactions beingconducted at temperatures in excess 'of 100 degrees centig rade forperiods of time varying between ten and 48 hours. On deacylating thehindered4-acylamidobenzoie acidester, the hindered 4 arninobenzoic acidester is obtained. This compound is then hydrolyzed by conventionalmeans to the corresponding hindered 4-aminobenzoic acid and the acid isacylated to obtain a hindered 4-acyla'rnidobenzoi'c 'acid. Acylatingagents which can be used include anhydrides of loweraliphatic acids suchas acetic anhyd ride, propionic anhydride, butyric anhydride, isobutyricanhydr'ide, and the like; arylsulfonyl halides suchas tosyl chloride,tosyl br'timid e, benzenesulfonyl chloride, and the like; and'aroylhalides such as benzoyl chloride, benzoyl bromide, and the like.

The hindered 4-acylamidobenzoicacid thus obtained is convertedto an acidhalide by reaction with'a'n inorganic acid halide such as thionylchloride, thionyl bromide, phosphorus trichloride,phosphoruspentachloride, phosphorus tribromide, phosphorus pentabromide,and the like. The conversion of the hindered 4-acylamidobenzoic acid tothe acid halide can be accomplished by any of the conventionalprocedures for forming acyl halides, e.g., in the presence of an inertsolvent such as benzene, toluene, and the like. Ordinari y, the hindered4-acylamidobenzoyl halide is obtained sufticiently pure for reactionpurposes merely by removing the inert solvent, although if desired,further purification can be efiected by conventional procedures such asvacuum distillation or recrystallization.

The resulting hindered 4-acylamidobenzoyl halide is reacted with acompound of thef'o'r'mula:

wherein Y, R and n are asdefined above. The reaction of the hindered4-acyl-amidobenzoyl halide with a secondary amino'alkylamine, or asecondary-aminoalkanol, or a secondary amino alkyl mercaptan, is similarto the reaction of an alkyl amine, alkanol, or alkyl mercaptan with anacyl halide. Preferably, the reaction is conducted between about zerodegrees centigrade and about forty degrees centigrade in thepresence ofan inert solvent such as benzene, toluene, and the like. Upon completionof the reaction, the resulting 4-acylamidobenzoic acid compound isisolatedby removalo'f the solvent, and can be further purifiedbyconventional means e.g., vacuum distillation.

The hindered 4 acylamidobenzoic acid compound thus obtained is thenselectively hydrolyzed to the corresponding hindered 4-aminobenzoic acidcompound by reaction with an alkali such as sodium hydroxide, potassiumhydioxide, and the like, in a solventsueh as a mixture of water with'alower-aliphatic alcohol,e.g., methyl alcohol, ethyl alcohol, propylalcohol, and the like, or with a watersoluble 'ketone such as acetone,methyl ethyl ketone, and the like. The hydrolysis is carried out'at atemperature between about forty degrees Centigrade and about 100 degreescentigrade, preferably between about fifty degrees centigrade' and about'degre'es'centigrade, and for a time between about one hour andabout'sixhours, preferably between about two hours and about four hours.From about one to about eight moles of alkali, and preferably from abouttwo to about six moles, are employed per mole of'startin'g4-acylamidobenzoic acid compound. In this hydrolytic reaction, care mustbe taken that hydrolysis of the amide group" in the 4-position iseffected without any substantialhydrolysis of the ester group in thel-position. Thus, when'ahigher reaction temperature, e.g., degreescentigrade is employed, and/ or a higher molar ratio of alkali tostarting amide-ester, e.g., 8:1, is employed, a correspondinglyshorterreaction time is employed, all of which will be readily apparent to oneskilled in the art.

When an arylsulfonyl halide or aroyl halide has been used'as theacylating agent, the corresponding hindered 4'-acylamidobenzoic acidcompound can be hydrolyzed by reaction with a mixture of hydrogenbromide and phenol in an acetic acid medium, by the procedure setforth'in US. Patent 2,562,222, to form the hindered 4- aminobenzoic acidcompound.

The process for the preparation of hindered 4-aminobenzoic acidderivatives is set forth in the following equations:

0 ll lYTHC R4 Hydroxyl- Halide amine salt (R40 0M0 Ra 0 O O R:

Hydrolysis and acylat ion wherein n is an integer from one to sixinclusive, R is a secondary amino radical, R is a member selected fromthe group consisting of hydrogen and alkyl, cycloalkyl, aralkyl, aryland heterocyclic radicals; R is a member selected from the groupconsisting of alkyl and aryl radicals; R is a member selected from thegroup consisting of hydrogen and alkyl and aralkyl radicals; R is analkyl radical; R is a member selected from the group consisting of alkyland aralkyl radicals; R is an acyl radical; X is halogen; and Y is amember selected from the group consisting of oxygen, sulfur, imino andalkylimino.

Examples of alkyl radicals are methyl, ethyl, propyl, butyl, amyl,hexyl, heptyl, octyl, and the like, including isomeric forms thereof.Cycloalkyl radicals include unsubstituted and substituted radicals suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, dimethylcyclohexyl, ethylcyclohexyl,amylcyclohexyl, hexylcyclohexyl, methylcyclobutyl, methylcyclopentyl,methylcyclooctyl, and the like, including isomeric forms thereof.Aralkyl radicals include unsubstituted and substituted radicals such asbenzyl, phenethyl, phenylpropyl, rnethoxyphenethyl, and the like,including isomeric forms thereof. Aryl radicals in clude unsubstitutedand substituted radicals such as phenyl, naphthyl, methoxyphenyl,butoxyphenyl, methoxynaphthyl, chlorophenyl, brornonaphthyl, tolyl,xylyl, trimethylphenyl, ethylphenyl, amylphenyl, methylbutylphenyl,methylnaphthyl, butylnaphthyl, diand trimethyl naphthyl, dichlorophenyl,dimethoxyphenyl, methoxychlorophenyl, and the like, including isomericforms thereof. Examples of heterocyclic radicals are furyl, thienyl,pyridyl, and the like, including isomeric forms thereof. Examples ofacyl radicals are acetyl, propionyl, butylryl, tosyl, benzenesulfonyl,benzoyl, and the like, including isomeric forms thereof. Examples ofhalogens are chlorine, bromine, and the like.

The starting materials of the invention, i.e., esters of hindered4-oxo-2-cyclohexene-l-carboxylic acids, are represented by the followingformula:

wherein R R R and R are as defined above, and include, for example:

Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,

n-amyl, l-ethylbutyl, benzyl, and phenethyl 2-methyl-4-oxo-2-cyclohexene-l-carboxylates,

Ethyl 2-ethyl-4oxo-2-cyclohexene-l-carboxylate,

Methyl 2-n-propyl-4-oxo-2-cyclohexene-l-carboxylate,

Methyl, benzyl, and phenethyl2,6-dimethyl-4-oxo-2-cyclohexene-l-carboxylates,

Methyl, ethyl, benzyl, and phenethyl 2-methyl-6-ethyl-4-oxo2-cyclohexene-1-carboxylates,

Methyl, ethyl, and benzyl Z-methyl-6-isopropyl-4-oxo-2-cyclohexene-l-carboxy1ates,

Methyl, ethyl, and benzyl 2,6-diethyl-4-oxo-2-cyclohexenel-carboxylates,1

Ethyl Z-methyl-6-n-hexyl-4-oxo-2-cyclohexene-l-carboxylate,

Ethyl 2-methyl-6-phenyl-4-oxo-2-cyclohexene-1-carboxylate,

Ethyl 2-rnethyl-6- (2-furyl) -4-oxo-2-cyclohexenel-carbox ylate,

Ethyl Z-methyl-6-cyclobutyl-4-oxo-2-cyclohexene-l carv boxylate,

Methyl Z-methyl-6-cyclohexyl-4-oxo-Z-cyclohexene-l-carboxylate, 4

Ethyl Z-methyl-6-o-methylbenzyl-4-oxo-2-cyclohexene-1- carboxylate,

Ethyl Z-methyl-6-p-methoxyphenethyl-4-oxo-2 cyclohexene-l-carboxylate,

Ethyl 2,6-diphenyl-4-oxo-2-cyclohexene-1-carboxylate,

Ethyl 2,6-diphenyl-3-ethyl-4-oxo-2-cyclohexene-1-carboxylate,

Ethyl 2,3-dimethyl-4-oxo-2cyclohexene-l-carboxylate,

Ethyl 2-methyl-3-benzyl-6-isopropyl-4-oxo-2-cyclohexenel-carboxylate,

Methyl 2,3,6-trimethyl-4-oxo-2-cyclohexene-l-carboxylate,

Ethyl 2-methyl-3-ethyl-4-oxo-2-cyc1ohexene-l-carboxylate,

Ethyl 2-methyl-3-(3,7-dimethyloctyl) -4-oXo-2-cyclohexene-l-carboxylate,I

Ethyl Z-methyl-3-m-methoxyphenethyl-4-oxo-2i-cyclohex ene-l-carboxylate,

Ethyl 2-methyl-3-ethyl-6-isopropyl-oxo-Z-cyclohexene-lcarboxylate,

Ethyl 2-ethyl-3-methyl-4-oxo-2-cyclohexene-l-carboxylate, Ethyl 2methyl-6-p-tolyl-4-oxo-2-cyclohexene-l-carboxylate, Ethyl2-methyl-6-benzyl-4-oxo-2-cyclohexene-l-carboxylate, Ethyl2-methyl-3-benzyl-4-oxo-2-cyclohexene-l-carboxylate, and the like.

The esters of hindered 4-oxo-2-cyclohexene-1-carboxylic acids which areused as starting materials in the synthesis of the novel compounds ofthe invention are prepared by various known methods.

For example, in one method, Knoevenagel condensation conditions areemployed to react aldehydes (e.g., formaldehyde, acetaldehyde,phenylacetaldehyde, isobutyraldehyde, furfural, hexahydrobenzaldehyde,and the like) with esters of p-keto alkanoic acids (e .g., ethyl aceto-:acetate, butyl acetoacetate, methyl acetoacetate, benzyl acetoacetate,ethyl propionylacetate, ethyl isobutyryl- 7 acetate, and the like) toform esters of a,a.'-diacylglutaric acids. These bis-esters," so-called,are then cyclized in various ways, e.g., with sulfuric acid and aceticacid, to produce esters of hindered 4-oxo-2-cyclohexene-l-carboxylicacids. This general method for preparing compounds of this type has beendescribed in the literature by Hagemann, Ber. 26, 876 (1893),

Horning, Denekas and Field, J. Org. Chem. 9, 547-551 Homing, Denekas andField,

L. I. Smith and Rouault, J. Am. Chem. Soc. 65, 631-635 (1943), and

W. T. Smith and Eftax, ibid. 75, 4356 (1953).

More specifically, on reacting 'formaldehyde with ethyl acetoacetate,ethyl 2-methyl-4-oxo-2-cyclohexene-l-carboxylate (Hagem-anns ester) isobtained; using acetaldehyde and ethyl propionylacetate as reactants,ethyl 2- ethyl 3,6-dimethyl-4-oxo-2-cyclohexene-l-canboxylate isobtained.

Similarly, other hindered 441xo-2-cyclohexene-l-carboxylicacid estersare obtained sue-has:

Ethyl 2,6-dimethyl-4-oXo-2-cyclohexene-l-carboxylate,

Ethyl 2-niethyl-6 ethyl=4-oxo 2-cyclohexene-l-carboxylate,

Ethyl 2 methyl 6 n hexyl-'-=-4 oxo 2 cyclohe'xene- Ethyl 2 methyl 6isopropyl 4 oxo 2 cyclohexenel car'bo'kylate,

Ethyl 2 methyl 6 n propyl 4 oxo 2 cyclohexene-ldarboxylate,

Ethyl 2 methyl 6 p methoxyphenethyl 4 oxo 2- cyclohexene l carboxylate,

Ethyl 2,6-diethyl-4-oxo-2-cyclohexene-l-carboxylate,

Beri'zyl 2,6 diethyl t oxo-2-cyclohexene-l-carboxylate,

Phenethyl 2,6 dimethyl 4 oxo 2 cyclohexene 1- c'arb'oirylate,

Ethyl 2 methyl 6 (2 furyl) 4 oxo 2 cyclohexene-l ':2'irbo tylate,

Ethyl 2 methyl 6 cyclohexyl 4 oxo 2 cyclohexrie l car'boxylate,

Methyl 2 methyl 6 cyclohexyl 4 -'oxo 2 cycloheXene-l-c'arboxylate, a

Ethyl '2 methyl -6 o rr'iethylhen'zyl 4 -oxo 2cyclohexene-l-carboxylate,

Butyl "2 -'ineth'yl --6 -be'nzyl 4 'oxo 2 cyclohexenel carbo'xylafe, andthe'like. --NeWman--and-Lloyd,'l'-.-Org. Chem. 17, 577-580 (1952),

utilized the diene synthesis to react 2-methoxybutadiene with ethyl 2butynoate to produce a cyclic enol ether which was readily converted bymild hydrolysis to Hagemann s ester. -Similarly,- starting cornpo'undsof the present invention can likewise be prepared'by this-method merelyby using-other 2-alkynoic acid esters as reactants to obtain compoundssuch as ethyl 2-ethyl-4-oXo-2-cyclohexene-l carb'oxylate, ethyl2-n-p'ropyl 4-oxo-Zkyclohexene-l-carboxylate, ethyl 2-n-b-utyl-4-oxo-2cyclohexene-lcarboxylate, and the like.

To prepare esters of hindered 4-oxo-2-cycloheXene-1- carboxylic acidshaving aryl substituents, it is ordinarily preferred toemployprocednressuchas those described by Rabe and Spence, Ann. 342, 352(1905),

Dieckmann and'Von-Fischer, Ber. "44, 966-974 (1911),

Dieckmann, ibid. 44,975-981 (1911), and

Homing and Field, J. Chem. Soc. 68, 387-389 Thus, bythesergeneralprocedures, esters of hindered 4- oxo-2-cyclohexene-l-carboxylic acidsare obtained such Ethyl -'-methyl 6-- p-methoXyphenyl-4- -oxo 2-cyclohexene-l-carborrylate,

Ethyl 2 rnethyl 6 phenyl 4-01:O Z-cycIoheXenc-l-carboxylate,

Org. Syntheses 27, 24-27 Ethyl2,6-diphenyl-4-oxo-2-cyclohexene-l-carboxylate, Ethyl2-methyl-6-p-tolyl-4-oxo-2-cyclohexene-l-carboxylate, and the like.

The esters of hindered 4-oxo-2-cyclohexene-1-carbox ylic acids, thestarting compounds for the process and products of the invention,wherein R is hydrogen (Formula 1, supra) are alkylated at position 3 toobtain corresponding compounds in which R is an alkyl or aralkylradical. Thus, for example, Hagemanns ester can be converted to ethyl2-methyl-3-pmethoxyphenethyl-4-oxo- 2-cyclohexene-1-carboxylate andethyl 2,6-dimethyl-4- oXo-2-cyclohexene-l-carboxylate can be convertedto ethyl 2,6 dimethyl 3 n butyl 4 oxo 2 cyclohexene-l-carboxylate.Suitable alkylation procedures :have been disclosed by Smith andRouault, supra, Bergmann and Weizmann, J. Org. Chem. 4, 266-269 Horning,Horning and Platt, I. Am. Chem. Soc. 71, 177 l- 1'773 (1949), l-Iorning,Homing and Walker, ibid. 71, 169-171 (1949),

Hogg, ibid. 70, 161-164 v 194s), Dieckmann, Ber. 45, 2701 (1912), andUS. Patent 2,582,252.

Thus, by these general procedures, other 'estersof hindered4-oXo-2-cyclohiexene-1 carboxylic acids are obtained "such Ethyl 2methyl 3 (3,7 dimethyloctyl) 4 oxo 2- cyclohexene-l-carboxylate,

Ethyl 2,3-dimethyl-4-oxo-2-cyclohexene-l-carboxylate,

Ethyl 2-r'nethyl-3 -ethyl-4-oxo-2-cyclohexenelcarboxylate,

Ethyl 2-methyl-3-m-methbxyphnethyl-4-oxo-2-cycldhexene-l-carboxylate,

Ethyl 2,6-dimethyl-3ethyl-4-oxo-2-cyclohexene-l-carbox- .ylate,

Ethyl 2-methyl-3-ethyl-6-isopropyl-4-oxo-2-cyclohexene-1- carboxylate,

Ethyl-2rnethyl-3-phenethyl-6-isopropyl-4-oxoQ-cyclohexene-l-carboxylate,

Methyl 2,3,6-trimethyl-4-oxo-2-cyclohexene-l-carboxylate,

Ethyl 2-ethyl-3-methyl-4-oXo-2 cyclohexene-1-carboxylate,

Ethyl 2-rnethyl-3-benzyl-4-oxo-Z-cyclohexene-l-carboxylate, and thelike.

The following examplesillustrate the process and products of the presentinvention but these examples are illust'rative only and are not to beconstrued as limiting.

'Example 1.-Efhy1 2,6-Dimethyl-4 Oximin0-2-Cycl0- hexene-l -Carb oxylate To'a solution {if-2 78 grams (410 moles) of 'hydroxylaminehydrochloride in 800 milliliters of pyridine and SOOmilliliters ofethanol is added 500 grams (3.0 moles) of ethyl 2,6-dirnethyl4-oXo-2-cyclohexene-l-carboxyl'ate. The solution is refluxed for fourhours. The solvents are removed under reduced pressure and a reddish gumwhich is thus obtained is dissolved in benzene. -'Ihe benzene solutionis washed with several portions of water, dried over magnesium sulfateand concentrated. An oily material which is thus obtained is distilledunder reduced pressure and the fraction of the desired ethyl2,6-dimethyl- 4-oximino-2-cyclohexene-l-carboxylate which distilsbetween and 162 degrees centigrade at 0.5 millimeter pressure iscollected. A yield of 485 grams (76.5 percent) of ethyl2,6-dimethyl-4-oximino-2-cyclohexene-1- carboxylate is obtained.

Analysis-Cale. for'C l-l 'fNo C, 62.52; H, 8.11; N, 6.63. Found: C,62.11; H, 8.04; N,-6.49.

Example 2.Ethyl 2-Me thyl-6-Ethyl-4-Oximin0-2-Cycl0- hexane-1 Carboxylate A mixture-of 26 grams (0.1-3 mole) of ethylZ-methyl- 6-ethyl 4oXo-Z-cyclohexene l-oarboxylate, 103 grams (0.15 mole) of hydroxylaminehydrochloride, and fifty Example 3.-Erlzyl2-Methyl-6-Is0pr0pyl-4-Oximin0-2- Cyclohexene-J -Carbxylale In athree-later, one-neck flask fitted with a reflux condenser are placed448.6 grams (2.0 moles) of ethyl 2- methyl 6 isopropyl 4 oxo 2cyclohexene 1 carboxylate, 278 grams (4.0 moles) of hydroxylaminehydrochloride, 700 milliliters of anhydrous pyridine and 500 millilitersof absolute ethanol. The mixture is refluxed for four hours and thenallowed to stand at 23 degrees centrigrade for fifteen hours. Thealcohol and pyridine are then removed from the mixture by distillationunder reduced pressure and the cooled residue dissolved in two liters ofether. The resulting solution is extracted with six one-liter portionsof water, dried over magnesium sulfate and then distilled. There isobtained 207 grams of ethyl2-methyl-6-isopropyl-4-oximino-2-oyclohexene-l-carboxylate (43 percentyield) boiling between 138 and 142 degrees centigrade at 0.3 millimeterpressure and characterized by an index of refraction 11 1.5070.

Analysis-Cale for C H NO N, 5.85. N, 5.82.

Similarly, on replacing ethyl2,6-dimethyl-4-oxo-2-cyclohexene-l-carboxylate in Example 1 by otherhindered 4-oxo-2-cyclohexene-l-carboxylic acid esters, other hindered4-oximino-2-cyclohexene-l-carboxylic acid esters are obtained. Thus, forexample, using ethyl 2-methy1- 4-oxo-2-cyclohexene-l-carboxylate as thestarting material, ethyl 2-methyl-4-oximino-2-cyclohexene-1-carboxyl ateis obtained; ethyl 2-ethyl-3,6-dimethyl-4-oximino-2-cyclohexene-l-carboxyla-te is obtained from ethyl Z-ethyl- 3,6dimethyl-4-oxo-2-cyclohexene-l-carboxylate; benzyl2,6-diethyl-4-oximino-Z-cyclohexene-l-carboxylate is obtained frombenzyl 2,6-diethyl-4-oxo-2-cyc1ohexene-1- carboxylate; ethyl2-methyl-6-(2-fury1)-4-oximino-2-cyclohexene-l-carboxylate is obtainedfrom ethyl 2-methyl- 6-(2-furyl)-4-oxo-2-cyclohexene-l-carboxylate;ethyl 2- methyl-6-cyclohexyl 4 oximino 2 cyclohexene-l-carboxylate isobtained from ethyl 2-methy1-6-cyclohexyl- 4-oxo 2cyclohexene-l-carboxylate; ethyl2-methyl-6-pmethoxyphenethyl-4-oximino-2-cyclohexene-1-carboxylate isobtained from ethyl 2-methyl-6-p-methoxyphenethyl-4-oxo-2-cyclohexene-1-carboxylate; ethyl 2,6-diphenyl-4-oximino-Z-cyclohexene-l-carboxylate is obtained from ethyl 2,6 diphenyl4 oxo-2-cyclohexene-1-carboxylate; and ethyl2-methyl-3-p-methoxybenzyl-4-oximino-2-cyclohexene-l-carboxylate isobtained from ethyl 2-methyl-3-p-methoxybenzyl-4-oxo-2-cyclohexene-l-carboxylate.

Similarly, using the procedure set forth in Example 1 except for thereplacement of ethyl 2,6-dimethyl-4-oxo- 2-cyclohexene-1-carboxylate byother hindered 4-oxo-2- cyclohexene-l-carboxylic acid esters, otherhindered 4- oximino-2-cyclohexene-1-carboxylic acid esters are preparedsuch as:

Found:

Phenethyl 2,6-dimethyl-4-oximino 2 cyclohexene-l-carboxylate,

Butyl 2 methyl-6-benzyl-4-oximino-2-cyclohexene-l-carboxylate,

Ethyl2-methyl-3-(3,7-dimethyloctyl)-4-oximino-2-cyclohexene-l-carboxylate,

Ethyl 2,6-diethyl-4-oximino-2-cyclohexene-l-carboxylate,

Ethyl 2-methyl-3-m-methoxyphenethyl-4-oximino-2-cyclohexene-l-carboxylate,

Ethyl 2-methyl-6-n-hexyl-4-oximino-Z-cyclohexene-l-carboxylate,

Ethyl 2-n-butyl-4-oximino-2-cyclohexene-l-carboxylate,

Ethyl 2 methyl-6-o-methylbenzyl-4-oximino-2-cyclohexene-1-carboxylate,

Ethyl2-methyl-6-p-methoxyphenethyl-4-oximino-2-cyclohexene-l-carboxylate,

Ethyl 2,6-dimethyl-3-ethyl 4 oximino-Z-cyclohexene-lcarboxylate,

Ethyl 2methyl-3-benzyl-6-isopropyl-4-oximino-Z-cyclohexene-l-carboxylate,

Ethyl 2-ethyl-4-oximino-2-cyclohexenel-carboxylate,

Ethyl 2 methyl-6-p-tolyl-4-oximino-Z-cyclohexene-l-carboxylate,

Ethyl 2,3 dimethyl-4-oximino-Z-cyclohexene-l-carboxylate, and the like.

Example 4.Ethyl 2,6-Dimethyl-4-Acetamidobenzoate 161 grams (0.76 mole)of ethyl 2,6-dimethyl-4-oximino- 2-cyclohexene-l-carboxylate (Example 1)is added to a cooled solution of 450 milliliters of acetic anhydride.Accompanied by stirring, the mixture is warmed to room temperature andthen allowed to stand for a period of about eighteen hours. 200milliliters of acetic acid is added to the mixture and a rapid stream ofdry hydrogen chloride gas is passed therethrough while heating to gentlereflux temperature. After six hours, at reflux temperature, the mixtureis cooled and poured, while stirring, onto ice. After allowing thecooled mixture to stand for about eighteen hours, a solid material whichseparates out is recovered by filtration and then dried over phosphoruspentoxide. A yield of 170 grams (95.5 percent) of ethyl2,6-dimethyl-4acetamidobenzoate is obtained which melts between 139 and140 degrees centigrade after recrystallization from methylcyclohexane.

Analysis-Cale. for C H NO C, 66.35; H, 7.28; N, 5.94. Found: C, 66.52;H, 7.37; N, 6.00.

Example 5 .-Ethyl-2-M ethyl-6-Ezhyl-4-A cetamidobeiizoaie 45 grams ofethyl Z-methyl-6-ethyl-4-oximino-2-cyclohexene-l-carboxylate (Example 2)is added to 150 milliliters of acetic anhydride. After allowing themixture to stand for a period of about eighteen hours, milliliters ofacetic acid is added and a rapid stream of dry hydrogen chloride gas ispassed through the mixture while heating to gentle reflux temperature.After about six hours at reflux temperature, the mixture is cooled andpoured, while stirring, onto ice. A solid material separates out whichis then recovered by filtration, washed with water and air dried. Afterrecrystallizing from methylcyclohexane, forty grams or ethyl2-methyl-6-ethyl- 4-acetamidobenzoate is obtained melting between and111 degrees centigrade.

Analysis-Cale for C14H19TIO2: C, 67.44; H, 7.68; N, 5.62. Found: C,67.28; H, 7.60; N, 5.74.

Example 6.Ethyl 2-Methyl-6-Is0pr0pyl-4-Acetamidobenzoate 151 grams (0.63mole) of ethyl 2-methyl-6-isopropyl-4-oximino-2-cyclohexene-1-carboxylate (Example 3) is added to a cooledsolution of 450 milliliters of acetic anhydride. After allowing themixture to stand for eighteen hours, 200 milliliters of acetic acid isadded and a stream of dry hydrogen chloride gas is passed therethroughwhile heating to gentle reflux temperature. After six hours at refluxtemperature, the mixture is cooled and poured, while stirring, onto ice.The cooled mixture is allowed to stand for about eighteen hours, duringwhich time a crystalline material separates out. The crystallinematerial is recovered by filtration, then washed with water, andrecrystallized from isopropanol. A yield of 56 grams (34 percent) ofethyl 2-methyl-6-isopropyl-4- ll acetamidobenzoate is obtained meltingbetween 98 and 99 degrees centigrade.

Amzlysis.-Calc. for CH21NO3: C, 68.61; H, 7.90; N, 5.99. Found: C,68.41; H, 8.04; N, 5.95.

Similarly, on replacing ethyl 2,6-dimethyl-4-oximino-Z-cyclohexene-l-carboxylate in Example 4 by other hindered4-oximino-2-cyclohexene-l-carboxylic acid esters and by reacting thesecompounds with acylating agents such as anhydrides of lower-aliphaticacids such as, for example, acetic anhydride, propionic anhydride,butyric anhydride, isobutyric anhydride, and the like, in the presenceoflower-aliphatic acid such as acetic acid, propionic acid, butyric acid,and the like, and a hydrogen halide, :other hindered 4-acylamidobenzoicacid esters are obtained. Thus, for example, on reacting ethyl .2-methyl-4-oximino-2-cyclohexene-l-carboxylate with acetic anhydride,acetic acid, and dry hydrogen chloride, ethyl2-methyl-4-acetamidobenzoate is obtained. In a like manner, ethyl2ethyl-3,6-dimethyl-4-propionamidobenzoate is obtained from ethylZ-ethyl 3,6-dirnethyl-4- oximino-Z-cyclohexene-l-carboxylate, propionicanhydride, propionic acid, and dry hydrogen bromide; benzyl2,6-diethyl-4-acetamidobenzoate is obtained from benzyl2,6-diethyl-4-oximino-2-cyclohexene-l-carboxylate, acetic anhydride,Valerie acid, and dry hydrogen chloride; ethyl 2methyl-6-(Z-furyl)-4-butyramidobenzoate is obtained from ethylZ-rnethyl-6-(2-furyl)-4-oximino-2 cyclohexene-l-carboxylate, butyricanhydride, butyric acid, and dry hydrogen chloride; ethyl.2-methyl-6-p-methoxyphenethyl-4-acetamidobenzoate is obtained fromethyl 2- methyl 6-p methoxyphenethyl-4-oxirnino-2-cyclohexenelcarboxylate, acetic anhydride, acetic'acid, and dry hydrogen chloride;ethyl 2,6-diphenyl-4-acetamidobenzoate is obtained from ethyl2,6-diphenyl-4-oximino-Z-cyclohexene-l-carboxylate, acetic .anhydride,acetic acid, and dry hydrogen chloride; ethyl 2-methyl-6-cyclohexyl-4-acetamidobenzoateis obtained from ethyl 2-methyl-6-cyclohexyl 4oximino-2-cyclohexene'l-carboxylate, acetic anhydride, acetic acid, anddry hydrogen chloride; and ethylZ-methyl-3-p-methoxyphenethyl-4-acetamidobenzoate is obtained from ethylZ-methyl-S-p-methoxyphenethyl-4-oximino-2-cyclohexene-l-carboxylate,acetic anhydride, acetic acid, and dry hydrogen bromide.

Similarly, other hindered 4-acylamidobenzoic acid esters are obtainedsuch as:

Example 7.2,6-Dimethyl-4-Aceaamidobenzoic Acid Fifteen grams (0.064mole) of ethyl 2,6-dimethyl-4- acetamidobenzoate (Example 4) is added toa solution of 35 grams (0.62 mole) of potassium hydroxide in 150milliliters of ethylene glycol. The mixture is heated to a temperaturebetween 160 and 170 degrees Centigrade and maintained within that rangefor a period of five hours. The solution is allowed to cool, then pouredinto 200 milliliters of water and the resulting solution is cooled in anice bath. While stirring, 25 milliliters of acetic anhydride is added tothe solution over a 45-minute period. A second 25-milliliter portion ofacetic anhydride is added to the mixture followed by the addition ofabout 25 milliliters of concentrated hydrochloric .acid. The solutionwhich :is now strongly acidic, is repeatedly extracted with ether togive about two liters of extractand the extract is then dried withanhydrous magnesium sulfate. After drying foreighteen hours, thesolution is filtered and concentnated to form a mixture of a solidmaterial and an oil. The mixture of solid material and oil is dissolvedin .25 milliliters of five percent sodium hydroxide solution, theresulting solution Washed with ether and the basic layer is acidified. Ayield of eight grams (60.5 percent) of 2,6-dirnethyl-4-acetamidobenzoicacid is obtained in the form of 'aprecipitate. The melting point of thiscompound, after recrystallization from ethyl acetate, is 214 to 216degrees centigrade.

A;za lysis.:Calc. for C H NO C, 63.76; H, 6.32; N, 6.76. Found: C,63.46; H, 6.27; N, 6.75. Example 8.2-Methyl-6-Ethyl-4-AcetamidobenzoicAcid Following the procedure described in Example 7 except for thereplacement of ethyl 2,6-dimethyl-4-acetamidobenzoate by ethyl,2emcthyl-6-ethyl-4-acetamidobenzoate (Example 5),Z-methyl-6-ethyl-4-acetamidobenzoic acid is obtained (96 percent yield)melting between 203 and 204 degrees Centigrade (tube).

Analysis.-Calc. 'for C H NO C, 65.14; H, 6.83; N, 6.33. Found: C, 65.15;H, 6.68g'N, 6.42.

Example 9.--2-Methylsfi-lsopropyll-acetamidobenzoic .Acid

Following the procedure described in Example 7 except for thereplacement of ethyl 2,6-dimethyl-4-acetamidobenzoate by ethyl,2-methyl-6-isopropyl-4-acetamidobenzoate (Example6),Z-methyl-6-isopropyl-4-acetamidobenzoicacidis obtained (sixty vpercentyield) melting between 194 and .197 degrees centigrade (tube).

Analysis-Called. vfor C13H17NO3: C, 66.58; H, 6.82; N, 5.99. Found: C,66.36; H, 7.13; N, 5.95.

Using the procedure described in Example 7 except for the replacement ofacetic anhydride by other acylating agents such as, acetyl chloride,acetyl bromide, propionyl chloride, propionic anhydride, butyricanhydride, butyryl chloride,.isobutyric anhydride, caproic anhydride,caproyl chloride, heptanoic anhydride, and the like; tosyl chloridep-toluenesulfonyl chloride), tosyl bromide (p-toluene-sulfonylbromide),'benzenesulfonyl chloride, and the like; benzoyl 'bromide,benzoyl chloride, and the like, other 2,6-dimethyl-4-acylamidobenzoicacids are ob tained. Thus,'by using propionic anhydride in the abovereaction, 2 ,6-dimethyl 4-propionamidobenzoic acid is obtained. In alike manner, 2,6-dimethyl-4 p-toluenesulionamidobenzoic acid is obtainedby the use of p-toluenesulfonyl chloride; 2;6-dimethyl-4benzenesulfonamidobenzoic acid is obtained by the use of benzenesulfonylchloride; and f2,6-dimethyl-4-benzamidobenzoic acid is obtained by theuse of benzoyl chloride. Ordinarily, it is preferred toutilize anacylating agent containing not more than seven carbon atoms and moreparticularly, an acylating agent derived from a lower-aliphaticmonocarboxylic acid containing not more than seven carbon atoms such asthe anhydrides or.acid halides of .said lower-aliphatic monocarboxylicacids.

.Similarly, orrreplacing ethyl 2,6-dimethyl-4-acetamidobenzoate. inExample 7. by other hindered 4-acylamidobenzoicacid esters, and by theuse of an acylating agent such as described supra, otherhinderedA-acylamidobenzoic acids are obtained. Thus, for example, by theuse of ethyl .Z-methyl-4-acetamidobenzoate, 2-methyl-4- acetamidobenzoicacid is obtained; 2-ethyl-3,6,-dirnethyl- 4-propionamidobenzoic acid isobtained by the use of ethyl2-ethyl-3,6-dimethyl-4-propionamidobenzoate; 2,6-diethyl-4-acetamidobenzoic acid is'obtained by the use of benzyl2,6-diethyl-4-acetamidobenzoate; 2-methyl-6-(Z-iuryl)-4-butyramidobenzoic acid'is obtained by the 13 use of ethyl2-methyl-6-(2-furyl)-4-butyramidobenzoate; 2 methyl 6 p-methoxyphenethyl4 acetamidobenzoic acid is obtained by the use of ethyl2-methyl-6-p-methoxyphenethyl 4 acetamidobenzoate; 2,6 diphenyl 4-acetamidobenzoic acid is obtained by the use of ethyl 5 2,6 diphenyl 4acetamidobenzoate; 2 methyl 6- cyclohexyl-4-acetamidobenzoic acid isobtained by the use of ethyl 2-methyl-6-cyclohexyl-4-acetarnidobenzoate;and 2 methyl 3 p methoxyphenethyl 4 acetamidobenzoic acid is obtained bythe use of ethyl 2-m-ethyl-3-p-meth- 1 oxyphenethyl-4-acetamidobenzoate.In the same manner, i.e., by replacing ethyl2,6-dimethyl-4-acetamidobenzoate in Example 7 by other hindered4-acylamidobenzoic acid esters, and by the use of an acylating agentsuch as described supra, other hindered 4-acylamidobenzoic acids areobtained such as:

. The deacylation step in Example 7 can be effected without producingany change in other positions on the ring by three alternativeprocedures such as (l), reacting the hindered 4-acylamidobenzoic acidester with a dilute aikali for a short period of time, e.g., about fourhours, or (2), alcoholysis or (3), ammonolysis, the alcoholysis andvammonolysis procedures being conducted at a temperature higher than 100degrees centigrade for periods of time varying between ten and 48 hours.By such procedures, hindered 4-aminobenzoic acid esters are obtainedsuch as:

Ethyl 2,6-dimethyl-4-aminobenzoate,

Methyl 2,6-dimethyl-4-aminobenzoate,

Benzyl 2,6-diethyl-4-aminobenzoate,

Ethyl 2-methyl-6-cyclohexyl-4-aminobenzoate,

Ethyl 2,6-diphenyl-4-aminobenzoate,

Ethyl 2-methyl-6-p-methoxyphenethyl-4-aminobenzoate, Ethyl2-methyl-6-n-hexyl-4-aminobenzoate,

Ethyl 2-methyl-4-aminobenzoate,

Ethyl 2-methyl-6-(2-furyl)-4-aminobenzoate,

Ethyl 2-ethyl-3,6-dimethyl-4-aminobenzoate,

Ethyl 2-methyl-6-o-methylbenzyl-4-arninoben2oate,

Butyl 2-methyl-6-benzyl-4-aminobenzoate, Ethyl2-methyl-6-p-methoxyphenethyl-4-aminobenzoate, Ethyl2-methyl-3-p-methoxyphenethyl-4-aminobenzoate, Ethyl2-methyl-6-isopropyl-4-aminobenzoate,

Ethyl 2, 6-diethyl-4-aminobenzoate,

Phenethyl 2, 6-dimethyl-4-aminobenzoate,

Ethyl 2-n-butyl-4-aminobenzoate,

Ethyl 2-methyl-3-(3,7-dimethyloctyl) -4-aminobenzoate, Ethyl2-methyl-3-m-methoxyphenethyl-4-aminobenzoate, Ethyl2,6-dimethyl-3-ethyl-4 aminobenzoate, 65 EthylZ-methyl-3-benzyl-6-isopropyl-4-aminobenzoate, Ethyl2-ethyl-4-aminobenzoate,

Ethyl 2-methyl-6-p-tolyl-4-aminobenzoate,

Ethyl 2,3-dimethyl-4-aminobenzoate, and the like.

' The hindered 4-aminobenzoic acid esters thus obtained are hydrolyzedto obtain the corresponding hindered 4-arninobenzoic acid such as:

2,6-dimethyl-4-aminobenzoic acid, 2,6-diethyl-4 aminobenzoic acid,

14 2-methyl-6-cyc1ohexyl-4-aminobenzoic acid,2,6-diphenyl-4-aminobenzoic acid, 2-ethyl-3,6-dimethy1-4-andnobenzoicacid, 2-methyl-6-n-hexyl-4-aminobenzoic acid, 2-methyl-4-aminobenzoicacid, 2-methyl-6- (2-furyl) -4-aminobenzoic acid,2-methyl-3-p-methoxyphenethyl-4-aminobenzoic acid,2-methyl-6-o-methylbenzyll-aminobenzoic acid,2-methyl-6-benzyl4-aminobenzoic acid,Z-methyl-6-p-rnethoxyphenethyl-4-aminozoic acid,Z-methyl-6-isopropyl-4-aminobenzoic acid, 2-n-butyl-4-aminobenzoic acid,2-methyl-3-benzyl-6-isopropyl-4-aminobenzoic acid,2-ethyl-4-aminobenzoic acid, Z-methyl-6-p-tolyl-4-aminobenzoic acid,2,3-dimethyl-4-amin0benzoic acid, 2-methyl-3-(3,7-dimethylocty1)-4-aminobenzoic acid, 2 methyl-3-m-methoxyphenethyl-4-aminobenzoic acid,2,6-dimethyl-3-ethy1-4-aminobenzoic acid, and the like.

The hindered 4-aminobenzoic acids thus obtained are then acylated withconventional acylating agents such as anhydrides of lower-aliphaticacids such as acetic anhydride, propionic anhydride, butyric anhydride,and the like, arylsulfonyl halides such as p-toluenesulfonyl chloride,p-toluenesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonylbromide, and the like, aroyl halides such as benzoyl chloride, benzoylbromide, and the like, to obtain the corresponding hindered4-acylamidobenzoic acids.

Example 10.2,6-Dimethyl-4-Acetamid0benz0yl Chloride In a dry, 2-liter,three-neck flask fitted with stirrer and reflux condenser are placed 207grams (1.01 mole) of 2,6-dlmethyl-4-acetamidobenzoic acid (Example 7),one liter of dry benzene and 179 grams (1.5 mole-110 milliliters) ofthionyl chloride. The mixture is stirred and slowly heated to reflux.When reflux temperature is reached, the reaction becomes somewhatviolent and must be controlled by cooling the container in an ice-bath.After the reaction has subsided, stirring and refluxing are continuedfor an additional 45 minutes. The mixture is cooled in an ice-bath forone hour and filtered. The solid material is washed with cold, drybenzene and dried in a vacuum desiccator. A yield of 192 grams percent)of 2,6-dimethyl-4-acetamidobenzoyl chloride is obtained melting betweenand 118 degrees centigrade.

Example 11.-2-Mezhyl-6-Ethyl-4-Acetamidobenzoyl Chloride Following theprocedure described in Example 10 except for the replacement of2,6-dimethyl-4-acetamido benzoic acid by2-methyl-6-ethyl-4-acetamidobenzoic acid (Example 8),2-methyl-6-ethyl-4-acetamidobenzoyl chloride is obtained.

Example 12.-2-Methyl-6-Is0pr0pyl-4-Acetamidobenzoyl Chloride Followingthe procedure described in Example 10 except for the replacement of2,6-dimethyl-4-acetamidobenzoic acid by2-methyl-6-isopropy1-4-acetamidobenzoic acid (Example 9),2-methyl-6-isopropyl-4-acetamidobenzoyl chloride is obtained.

Similarly, using the procedure of Example 10 except for the replacementof 2,6-dimethyl-4-acetamidobenzoic acid by other hindered4-acy1amindobenzoic acids, other hindered 4-acylamidobenzoyl chloridesare obtained. Thus, for example, on reacting 2,6dirnethyl-4-propionamidobenzoic acid with an inorganic acid chloride,2,6 dimethyl-4-propionamidobenzoyl chloride is obtained. In a likemanner, 2,6-dimethyl-4-p-toluenesulfonamidobenzoyl chloride is obtainedby reacting 2,6-dimethyl-4- p-toluenesulfonamidobenzoic acid with aninorganic acid chloride; 2,6-dimethyl 4 benzenesulfonamidobenzoylchloride is obtained by reacting2,6-dimethyl-4-benzenesulfonamidobenzoic acid with an inorganic acidChlo ride; 2,6-dimethyl-4-benzamidobenzoyl chloride is obtained byreacting 2,6-dimethyl-4rbenzamidobenzoic acid with an inorganic acidchloride; 2-methyl-4-acetamidobenzoyl chloride is obtained by reacting2-rnethyl-4- acetamidobenzoic acid with an inorganic acid chloride;2-ethyl-3,6-dimethyl-4-propionamidobenzoyl chloride is obtained byreacting 2-ethyl-3,6 dimethyll propionamidobenzoic acid with aninorganic acid chloride; 2,6-methyl 4-acetamidobenzoyl chlonde isobtained by reacting 2,6, diethyl-4-acetamidobenzoic acid with aninorganic acid chloride; 2-methyl-6-(Z-furyl)r-4ebutyrarnidobenzoylchloride isobtained by reacting -2-methyl-6-(2-furyl)e l-bntyl:-amidobenzoic acid with an inorganic acid chloride; 2;methyl-6-p-methoxyphenethyl-4 acetamidobenzoyl chloride is obtained byreacting 2-rnethyl-6-p-methoxyphenethyl-4-acetamidobenzoic acid with aninorganic acid chloride; 2,-diphenyl-4-acetarnidobenzoyl chloride is ob:tained by reacting 2,6-diphenyl-4-acetamidobenzoic acid with aninorganic acid chloride; 2-rnethyl-ficyclohexyle4- aeetamidobenzoylchloride is obtained by reacting 2- methyl-6-cyclohexyl-4acetamidobenzoic acid with an inorganic acid chloride; and2-rnethyl-3-p-rnethoxyphenethyl-4-acetamidobenzoyl chloride is obtainedby reacting 2-methyl-3-p-methoxyphenethyl-4 acetamidobenzoic acid withan inorganic acid chloride.

'In the same manner, on replacing 2,6-dimethyl-4-acetamidobenzoic acidin EXample 10 by other hindered 4- aeylamidobenzoic acids there areobtained:

2-methyl-6-n-hexyl-4-acetamidobenzoyl chloride,2-methyl-6-isopropyl-4-propionarnidobenzoyl chloride,2-methyl-6-p-methoxyphenethyl-4-butyramidobenzoyl chloride,2,6-diethyl-4-isobutyramidobenzoyl chloride,2-methyl-6-o-methylbenzyl-4-acetamidobenzoyl chloride, Z-methyl-6benzyl-4-acetamidobenzoyl chloride, 2-ethyl-4-acetamidobenzoyl chloride,Z-n-butyl-4-acetamidobenzoyl chloride,2-methyl-6-p-tolyl-4-acetamidobenzoyl chloride, Z-methyl-3(3,7-dimethyloctyl)-4-acetamidobenzoy1 chloride,2,3-dimethyl-4-acetamidobenzoyl chloride,2-methyl-3-m-rnethoxyphenethyl-4-acetamidobenzoyl chloride,2,6-dimethyl-3-ethyl-4-acetamidcbenzoyl chloride,Z-rnethyl-3benzyl-6-isopropyl-4-acetamidobenzoyl. chloride, and thelike.

It should be noted that by replacing thionyl chloride in the aboveindicated procedure by phosphorus trichlon'de, phosphorus pentachloride,or the like, hindered 4- acylamidobenzoyl chlorides are also obtained.

Similarly, by using thionyl bromide, phosphorus tribromide, phosphoruspentabrornide, or the like, the corresponding hindered4-acylamidobenzoyl bromides are obtained.

Example 13.--N-fi-Diethy laminethy[-2,6-Dimethyl- 4 -Acetamid0benzamideIn a dry SOO-milliliter, three-neck flask fitted with a stirrer,reflux-condenser and dropping funnel areplaced forty grams,(0.l7 8 mole)of 2,6-dimethyl-4-acetamidobenzoyl chloride (Example 10) and 200milliliters of dry benzene. The mixture is stirred and cooled in anicebath while adding dropwise, over a one hour period, 46.5 grams (0.4mole). of .fi-diethylaminoethylamine dissolved in 100 milliliters of drybenzene. The mixture is stirred, while maintained at a temperature of 25degrees centigrade, for twentyhours. Thebenzene is .rernoved bydistillation and .a viscous, oily product is obtained. This material isdistilled in vacuo and the main fraction boiling between 190 and 210degrees centigrade at- 0.01 millimeter pressure, which is identifiedbyinfrared analysis as N-fi-diethylaminoethyl-2,6dimethyl-4-acetamidobenzamide, is recovered.

16 Example 14.-N-B-Diethylamin0ethyl-2-Methyl-6-Ethyl-4-Agetamid0benzqmide Following the procedure described in Example13 except for the substitution of 2,6-dfmethyl-4-acetamidobenzoylchloride by 2-methyl-6-ethyl4-acetamidobenzoyl chloride (Example 11),N-B-diethylaminoethyl-Z-rnethyl- 6-ethyl-4-acetaniidobenzamide isobtained.

Example l5.--N-5-Diethylaminoetlzyl-Z-Methyl-filsopropyl-4Acetqmidobenzamide Following the procedure described in Example 13except for the substitution of 2,6-dimethyl-4-acetamidobnzoyl chlorideby 2-methyl-fi-isopropyl-4-acetamidobenioyl chloride (Example 12.),N-B-diethyIannnQethyl-Z- methyl-6-isopropyl-4-acetamidobenzamide isobtained.

Following the procedure described in Example 13 except for thereplacement of B-diethylaminoethylamine by other secondary'aininoalkylamines, other hindered 4- acylamidobenzamides are obtained. Thus,for example, on reacting 2,fi-dirnethyl-4-acetainidobenzoyl chloridewith diethylaminomethylamine,N-diethylarninomethyl-2,6-dirnethyl-4-acetamidobenzamide is obtained. Ina like manner, N-zeta-dietl'iylaminohexyl-2,fi-dimethyl 4acetamidobenzamide is obtained .by reacting 2,6-dimethyl-4-acetamidobenzoyl chloride with aeta-diethylaminohexylamine; Nfimethylcyclohexylaminoethyl-2,6-dimethylA-acetamidoberizamide is obtainedby reacting 2,6-dimethyl-4-acetamidobenaoyl chloride with fi-rnethylcyclohegrylaminoethylamingN.- methy1,- N-'ediethylamirioethyl-2,6-dirnethyl4eacetamidobenzamide is obtained byreacting ;2, 6- dirnethy1-4-acetarnidoben2oyl chloride with N methyl N Bdieth ylaminoethylamine; .N (B- methylcyclohexylaminoethyl) N ethyl 2,6diinethyl- 4 -acet-amidobenzarnide is obtained by reacting2,6-dimethyl-4 acetamidobenzoyl chloride with N-ethyl-N-(pmethylcyclohexylaminoethyl) amine; N 6 (1 pyrrolidyl)ethyl-Z,6-dimethyl-4-acetamidobenzamide is obtainedby reacting2,6-dimethyb4-acetamidobenzoyl chloride with {Hl-pyrrolidyD-ethylamine;N-fi-(LZ-dimethyll-pyrrolidyl1ethyl-2,6 dimethyl-4-acetamidobenzarnideis obtained by reacting2,6-dimethyl-4-acetamidobenzoyl chloride withfi-(2,2 dirnethyll pyrrolidyl)-ethylamine; N B (1 piperidyl)ethyl 2,6dimethyl 4 acetamidobenzamide is obtained by reacting2,6-dimethyl-4-acetamidobenzoyl chloride withfl-(l-piperidyl)ethylamine; N i3 (2 methyl .1 piperidyl)ethyl 2,6dimethyl-4- acetamidobenzamide is obtained by reacting 2,6-dimethyl-4-acetamidobenzoyl chloride with B-(Z-methyl-l-piperidy1)ethylamine; Nbntyl N q (1 piperidyl)- propyl-2,6-dimethyl-4-acetarnidobenzamide isobtained by reacting 2,6-dimethyla4-acetamidobenzoyl chloride with Nbntyl N 'y (1 piperidyDpropylamine; N ,3 (4- morpholinyl)ethyl-2,6dimethyl-4eacetamidobenzamide is obtained by reacting2,6-dimethyl-4-acetamidobenzoyl chloride .with'fi(4.-morpholinyl)eethylamine; N-;8(-2- methyl 4 morpholinyl)ethyl 2,6dirnethyl-4eacetamidobenzamide is obtained by reacting 2,6-dimethyl-4-acetamidobenzoyl chloride .with 1&(2-methyl-4-rnorpho- IinyDethyIamine;N -p .methylethylaminoethyl 2,6- dimethyl-4-acetarnidobenzamide is.obtained by reacting 2,6-dirnethyl-4-acetamidobenzoyl chloride withp-methylethylaminoethylamine; and N-fi-diisopropylaminopropyl-2,6-dimethyl-4-acetamidobenzamide is obtained by reacting2,6-dimethyl-tacetamidobenzoyl chloride with ,3-diisopropylaminopropylamine.

Similarly, on reacting fi-diethylaminoethylarnine with other2,6-dimethyl-4-acylamidobenzoyl halides in the manner set forth inExample 13, other N-substituted 2,6- dimethyl-4-acylamidobeniamides areobtained. Thus, for example, on reacting 2,6-dimethyl4-propionamidobenzoyl bromide with fl-diethylaminoethylamine,N-fi-diethylaminoethyl 2,6 dimethyl 4 propionamidobenzamide is obtained.In a-liltemanner, N-fi-diethylaminoethyl 2,6 dimethyl 4p-toluenesulionamidobenzaniide 17 is obtained from2,6-dimethyl-4-p-toluenesulfonamidobenzoyl chloride; N--diethylaminoethyl-,6-dimethyl-4- benzenesulfonamidobenzamide isobtained from 2,6-dimethyl-4-benzenesulfonarnidobenzoyl chloride; and N-diethylaminoethyl-Z,6-dimethyl-4-benzamidobenzamide is obtained from2,6-dimethyl-4-benzarnidobenzoyl chloride.

Following the procedure described in Example 13 except for thesubstitution of 2,6-dimethyL4-acetamidobenzoyl chloride by otherhindered 4-acylamidobenzoyl halides, other hindered4-acylamidobenzamides are obtained. Thus, for example, on reacting,G-diethylaminoethylamine with 2-methyl-4-acetamidobenzoyl chloride, N,6 diethylaminoethyl 2 methyl 4 acetamidobenzarnide is obtained. In alike manner, N-B-diethylaminoethyl 2 ethyl 3,6 dimethyl 4propionamidobenzamide is obtained by reacting ,B-diethylaminoethylaminewith 2-ethyl-3,6-dimethyl-4-propionamidobenzoyl bromide; N Bdiethylaminoethyl 2,6 diethyl 4- acetamidobenzamide is obtained byreacting B-diethylaminoethylamine with 2,6-diethyl-4-acetamidobenzoylchloride; N ,6 diethylaminoethyl 2 methyl 6 (2furyl)-4-butyramidobenzamide is obtained by reacting B-diethylaminoethylamine with 2-methyl-6-(2-furyl) 4- butyramidobenzoylchloride; N-fi-diethylaminoethyl-Z- methyl 6 p methoxyphenethyl 4acetamidobenzamide is obtained by reacting B-diethylaminoethylamine with2-methyl-6-methoxyphenethyl 4 acetamidobenzoyl chloride; N ,8diethylaminoethyl 2,6 diphenyl 4- acetamidobenzamide is obtained byreacting B-diethylaminoethylamine with 2,6-diphenyl-4-acetamidobenzoylchloride; N 3 diethylaminoethyl 2 methyl 6cyclohexyll-acetamidobenzamide is obtained by reacting B-diethylaminoethylamine with 2-methyl-6-cyclohexyl-4- acetamidobenzoylchloride; and N-fi-diethylaminoethyl-2-methyl-3-p-n1ethoxyphenethyl-4-acetamidobenzamide is obtained byreacting ,B-diethylaminoethylamine with 2methyl-3-p-rnethoxyphenethyl-4-acetamidobenzoyl chloride.

Similarly, on replacing 2,6-dimethyl-4-acetamidobenzoyl chloride inExample 13 by other hindered 4-acylamidobenzoyl halides, other hindered4-acylamidobenzamides are obtained such as:

N-fi-diethylaminoethyl-Z-methyl-6-nhexyl-4- acetamidobenzamide,N-fi-diethylaminoethyI-Z-methyl-6-isopropyl-4- propionamidobenzamide,N-B-diethylaminoethyl-Z-methyl-6-p-methoxyphenethyl-4-butyramidobenzamide, N-,8-diethylaminoethyl-Z,6-diethyl-4-isobutyramidobenzamide,N-B-diethylaminoethyl-Z-methyl-6-o-methylbenzyl-4- acetamidobenzamide,N-fl-diethyiaminoethyl-2-methyl-6-benzyl-4- acetamidobenzamide,N-B-diethylaminoethyl-Z-ethy1-4-acetamidobenzamide,N-fi-diethylaminoethyl-2-n-butyl-4-acetamidobenzamide,N-fi-diethylaminoethyl-Z-methyl-6-p-tolyl-4- acetamidobenzamide, N-fi-diethylaminoethyl-Z-methyl-3- 3,7 -dimethyloctyl)4-acetamidobenzamide, N-fl-diethylaminoethyl-2,3-dimethyl-4-acetamidobenzamide, N-;3-diethylaminoethyl-Z-methyl-3m-methoxyphenethyl- 4acetamidobenzamide,N-e-diethyIaminoethyI-Z,6-dimethyl-3-ethyl-4- acetamidobenzamide,N-fi-diethylaminoethyl-2-rnethyl-3-benzyl-6-isopropyl-4-acetamidobenzamide, and the like.

Example J6.,8-Diethylamz'noethyl 2,6-Dz'metIzyl-4-Acetamidobenzoate In adry IOU-milliliter, one-neck flask fitted with a refiux condenser,dropping funnel and drying tube is placed twenty grams (0.0885 mole) of2,6-dimethyl-4-acetamidobenzoyl chloride (Example 10). Over a thirtyminute period, 44 grams of e-diethylaminoethanol is added there to. Themixture is heated on a steam bath for twenty hours at a temperature of190 degrees centigrade, cooled to twenty degrees centigrade and 200milliliters of water is added thereto. The solution is made basic withsodium hydroxide pellets, then extracted with ether and the ether layerthen dried. The ether is removed by distillation and the brown, viscousoily residue solidifies upon cooling. There is obtained 18.8 gramspercent yield) of fi-diethylaminoethyl 2,6-dimethyl-4-acetamidobenzoatemelting between 89 and 91 degrees centigrade (tube) afterrecrystallization from methylcyclohexane.

Analysis.Calc. for C H N O C, 66.63; H, 8.55; N, 9.14. Found: C, 66.67;H, 8.65; N, 8.93.

Example 17.,B-4-M0lph0linylethyl 2,6-Dimethyl-4-AcetamidobenzoateExample J8. 3-1-Piperidylethyl 2,6 -D im etlzyl-4-A cetam idobenzoateFollowing the procedure described in Example 16 except for thesubstitution of fl-diethylaminoethanol by fi-l-piperidylethanol, thereis obtained ,B-l-piperidylethyl 2,6-dimethyl-4-acetamidobenzoate meltingbetween 134 and 135 degrees centigrade (tube) after recrystallizationfrom methylcyclohexane.

Example 19.--B-Diethylaminocthyl 2-l/Iethyl-6-Ethyl-4- AcetamidobenzoareFollowing the procedure described in Example 16 except for thereplacement of 2,6-dimethyl-4-acetamidobenzoyl chloride byZ-methyl-6-ethyl-4-acetarnidobenzoyl chloride (Example 11),,B-diethylaminoethyl 2-methyl-6- ethyl-4-acetamidobenzoate is obtained.

Example 20.,B-Dietlzylaminoethyl Z-Methyl-tS-Isopropyl-4-Acetamidobenzoate ncnn non wherein R is a secondary-amino radical, andn is an in teger from one to six inclusive, the corresponding 2,6-dimethyl-4-acylamidobenzoic acid esters are obtained, Suitablesecondary-amino alkanols include dialkylaminoalkanols suchlas, forexample, B-diinethylamincethanol, dimethylaminomethanol,diethylaminomethanol, B-diethylaminopropanol, 'y-diethylaminopropanol,,8diethylaminobutanol, B-diethylaminobutanol, e-diethylarninopentanol,zeta-diethylaminohexanol, B-dipropylaminoethanol,e-diisopropylaminoethanol, fl-dipropylaminopropanol,'y-dipropylaminopropanol, e-dibutylaminoethanol,,B-dibutylaminopropanol, fl-methyle-thylaminoethanol,fi-methylpropylaminoethanol, ,e-methylhexylaminoethanol, and the like;dicycloalklaminoalkanols such as, for example,fl-dicyclopentylaminoethanol, ,8 dicyclohexylaminoethanol, and the like;alkyl aralkylaminoalkanols such as, for example,methylbenzylaminornethanol, fi-ethylbenzylaminoethanol,p-propylbenzylaminoethanol, and the like; alkylcycloalkylaminoalkanolssuch as, for example, ,B-methyh cyclohexylaminoethanol, and the like;diaralkylaminoalkanols such as, for example, B-dibenzylaminoethanol,{i-diphenethylaminoethanol, and the like; heterocyclic aminoalkanolssuch as, for example, l-pyrrolidylmethanol, fi-l-pyrrolidylethanol,fi-l-pyrrolidylbutanol, and the like; carbon-substitutedpyrrolidylalkanols, piperidylalkanols, morpholinylalkanols, such as, forexample, B-(Z-methyl-lpyrrolidyl) ethanol, 8-(2,2-dimethyl-l-pyrrolidyl) ethanol, B-(Z-ethyl-l-pyrrolidyl)ethanol,;3(2-, 3-, and 4-methyll-piperidyDethanols, ,8-(2-, 3-, and4-ethy1-1-piperidyl)- ethanols, fi-(2-, and3-methyl-4-morpholinyl)ethanols, ,8 (2-, and3-ethyl-4-morpholinyl)ethanols, and the like.

Following the procedure described in Example 16 except for thereplacement of fi-diethylaminoethanol by other secondary-amino alkanols,the following 2,6-dimethyl-4-acetamidobenzoic acid esters are obtained:

Zeta-diethylaminohexyl 2,6-dimethyl-4-acetamidobenzoate,

p-Mrethylethylaminoethyl 2,6-dirnethyl-4-acetamidobenzoate,

fl-Dicyclohexylaminoethyl 2,6-dimethy1-4-acetamidobenzoate,

fl-Ethylbenzylaminoethyl 2,6-dimethyl-4-acetamidobenzoate,

B-Dibenzylaminoethyl 2,6-dimethyl-4-aeetamidobenzoate,

B-I-pyrrolidylethyl 2,6-dimethyl-4-acetamidohenzoate,

p-(2-methyl-1-pyrrolidyl)ethyl 2,6-dimethyl-4-acetamid0:

benzoate,

18-(2-met'nyl-1-piperidyl)ethy1 2,6-dimethyl-4-acetamidobenzoate,

p Q-rnethyl-4-morpholinyl)ethyl 2,6-di1'nethyl-4-acetamidobenzoate.

Similarly, on reacting fl-diethylamioethanol with other2,6-dirnethy1-4-acylamidobenzoyl halides in the manner set forth inExample 16, the following 2,6-dimethyl-4- acylamidobenzoic acid estersare obtained:

pDiethylaminoethyl 2,6-dimethyl-4-propionamidobenzoa-te,

fl-Diethylaminoethyl 2,6-dimethyl-4-butyramidobenzoate,

B-Diethylaminoethyl 2,6-dimethyl-4-p-toluenesulfonamidobenzoate,

(S-Diethylaminoethyl 2,6-dimethyl-4-benzenesulfonamidobenzoate,

fi-Diethyla-minoethyl 2,6-dimethyl-4 benzamidobenzoate,

and the like.

Following the procedure described in Example 16 except for thesubstitution of 2,6-dirnethyl-4-acetamidobenzoyl chloride by otherhindered 4-acylamidobenzoyl halides, other hindered 4-acylamidobenzoicacid esters are obtained such as:

6-n-hexyl 4-acetamido- ,B-Diethylaminoethyl2methyl-6-benzyl-4-acetamidobenzoate,

B-Diethylaminoethyl 2'ethy1-4-acetamidobenzoate,

ii-Diethylaminoethyl 2-n-butyl-4-acetamidobenzoate,

e-Diethylaminoethyl 2methyl-6-p-tolyl-4-acetamidobenzoate,

fi-Diethyiaminoethyl 2-methy1-3 (3,7-dimethylocty1)-4-acetamidobenzoate,

p-Diethylaminoethyl 2,3-dimethyl-4-acetamidobenzoate,

fi-Diethylaminoethyl 2-methyl-3 -m-methoxyphenethyl-4-acctamidobenzoate,

fl-Diethylamiuoet-hyl 2,6-dimethyl-3-ethyl-4- acetamidobenzoate,

B-Diethylaminoethyl 2-methyl-3-benzyl-6-isopropyl-4- acetamidobenzoate,and the like.

Following the procedure described in Example 13 except for thereplacement of p-diethylaminoethylamine by compounds of the generalformula:

wherein R is a secondary amino radical, and n is an integer from one tosix inclusive, the corresponding 2,6- dirnethyl-4-acylamidothiolobenzoicacid esters are obtained. Suitable secondary-amino lower alkylmereaptans include, for example, fl-dimethylaminoethyl mercaptan,p-diethylaminoethyl mercaptan, ,B-diethylaminopropyl mercaptan,'y-diethylaminopropyl mercaptan, zetadiethylaminohexyl mercaptan,B-dipropylaminoethyl mereaptan, fi-rnethylethylaminoethyl mercaptan,,B-nethylpropylaminoethyl mercaptan, and the like;dicycloalkylaminoalkyl mercaptans such as, for example,fl-dicyclopentylaminoethyl mercaptan, /3dicyclohexylaminoethylmercaptan, and the like; alkyl-aralkylamino mercaptans such as, forexample, methylbenzylaminoethyl mercaptan, fi-ethylbenzylaminoethylmercaptan, and the like; diaralkylarninoalkyl mercaptans such as, forexample, fi-dibenzylaminoethyl mercaptan, e-diphenethylaminoethylmercaptan, and the like; heterocyclic aminoalkyl mercaptans such as, torexample, l-pyrrolidylmethyl mercaptan, fi-l-pyrrolidylethyl mercaptan,a-l-pyrrolidylbutyl mercaptan, fl-l-piperidylethyl mercaptan, 5-4-rnorpholinylethyl mercaptan, and the like; carbon-substitutedpyrrolidylalkyl-, piperidylalkyl-, and morpholinylalkyl mercaptans suchas, for example, Q-(Z-methyl-l-pyrrolidyl)ethy1 mercaptan,B-(LZ-dimethyl-l -pyrrolidyl) ethyl mercaptan,6-(2-ethyl-1-pyrrolidyl)ethyl mercap tan, 542-, 3-, and4-methy1-1-piperidy1)ethyl mercaptans, B-(2-, 3-, and4-ethyl-1-piperidyl)ethyl mercaptans, {3-(2- and3-methyl-4-morpholinyl)ethyl mercaptans, ,8-(2- and3-ethyl-4-morpholinyl)ethyl mercaptans, and the like.

Following the procedure described in Example 13 except fior thereplacement of B-diethylaminoethylamine by secondary-amino alkylmercaptans, the following 2,6- dimethyl-4-acetamidothiolobenzoic acidesters are obtained B-Diethylaminoethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

Zeta-diethylaminohexy-l 2,6-dimethyl-4-acetarnidothioloibenzoate,

,B-Methylethylaminoethyl 2,6-dimethylt-acetamidothiolobenzoate,

fl-Dicyclohexylaminoethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

3-Ethylbenzylaminoethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

fi-Dibenzylaminoethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

fi-l-vpyrrolidylethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

fl-l-piperidylethyl 2,6-dimethyl-4-acetamidothiolobenzoate 5-4morpholinylethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

8- Z-methyll-pyrrolidyl) ethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

S-(Z-methyl-l-piperidyl) ethyl 2,6-dimethyl-4-acetamidothiolobenzoate,

8- 2-methyl-4-morpholinyl ether 2,6-dimethy1-4-acetamidothiolobenzoate,and the like.

Similarly, on reacting B-diethylaminoethyl mercaptan with other2,6-dimethyl-4-acylamidobenzoyl halides in the manner set forth inExample 13, other 2,6-dimethyl- 4-acylamidothiolobenzoic acid esters areobtained such as:

p-Diethylaminoethyl 2,6-dimethyl-4-benzamidothiolobeuzoate, and thelike.

Following the procedure described in Example 13 except for thereplacement of fi-diethylarninoethylamine by fi-diethylaminoethylmercaptan and the substitution of 2,6-dimethyl-4-acetamidobenzoylchloride by other hindered 4-acylamidobenzoyl halides, other hindered 4-acylamidothiolobenzoic acid esters are obtained such as:

(3-Diethylan1inoethy1 2-methyl-4-acetamidothiolobenzoate,

e-Diethylaminoethyl 2-ethyl-3,6-dimethyl-4-propionamidothiolobenzoate,

fi-Diethylaminoethyl 2,6-diethyl-4-acetamidothiolobenzoate,

fi-Diethylaminoethyl 2-methyl-6-(2-furyl)-4-butyramidothiolobenzoate,

fl-Diethylaminoethyl Z-methyl-6-p-methoxyphenethyl-4-acetamidothiolobenzoate,

fl-Diethylaminoethyl 2,6-diphenyl-4-acetamidothiolobenzoate,

,B-Diethylaminoethyl 2-methyl-6-cyclohexy1-4-acetamidothiolobenzoate,

S-Diethylaminoethyl 2-methyl-3-p-methoxyphenethyl-4-ace-tamidothiolobenzoate,

fl-Diethylaminoethyl Z-methyl-6-n-hexy-4-acetamidothiolobenzoate,

fi-Diethylaminoethyl Z-methyl-6-isopropyl-4-propi0narnidothiolobenzoate,

p-Diethylaminoethyl Z-methyl-6-p-methoxyphenethyl-4-butyramidothiolobenziate,

fi-Die'thylaminoethyl 2,6-chethyl-4-isobutynamidothiolobenzoate,

B-Diethylaminoethyl 2-methyl-6-o-methoxybenzyl-4.

acetamidothiolobenzoate,

fl-Diethylaminoethyl Z-methyl-6-benzyl-4-acetamidothiolobenzoate,

fl-Diethylaminoethyl S-Diethylaminoethyl zoate,

e-Diethylaminoethyl thiolobenzoate,

fi-Diethylaminoethyl 2-methyl-3- 3,7-dimethyloctyl)4-acetamidothiolobenzoate,

3-Diethylaminoethyl 2,3-dimethyl-4-acetarnidothiolo benzoa-te,

fi-Diethylaminoethyl 2-methyl-3-m-methoxyphenethyl-4-acetamidothiolobenzoate, I

S-Diethylam-inoethyl 2,6-dimethyl-3-ethyl-4-acetamido thiolobenzoate,

fl-Diethylaminoethyl 2-methyl-3-benzyl-6-isopropyl-4-acetamidothiolobenzoate, and the like.

Example 21.N-[3-Diezhylamin0ethyl-2,6-Dimethyl-4- Amiizobenzamide2-ethy1-4-acetamidothiolobenzoate, Z-n-butyl-4-acetamidothioloben-2methyl-6-p-tolyl-4-acetamido In a two-liter, one-neck flask fitted witha reflux condenser are placed the N--diethylaminoeLhyl-2,6-dimethyl-4-acetamidobenzamide obtained in Example13, forty grams of sodium hydroxide, milliliters of water and 500milliliters of ethyl alcohol. The mixture is refluxed for three hoursand then allowed to cool at room temperature overnight. The alcohol andwater mixture is evaporated under vacuum on a steam bath and the solidresidue thus obtained is extracted With ether. The ether extract isfiltered, dried and then distilled. The fraction boiling between anddegrees cen'tigrade at 0.02 millimeter pressure is collected andidentified as N- ,B-diethylarninoethyl-2,6-dirnethyl-4-aminobenzarnide.

On heating a benzene solution ofN-fi-diethylaminoethyl-2,6-dirnethyl-4-aminobenzamide and methyl bromideand cooling and concentrating the resulting solution, N 9diethyl-aminoethyhZ,6-dimethyl-4-arninobenzamide methobrornide isobtained.

Similarly, by reactingN-fi-diethylaminoethyl-2,6-dimethy1-4-aminobenzamide with other esterssuch as ethyl chloride, benzyl chloride, and the like, the corresponding quaternary ammonium salts ofN-B-diethylaminoethyl-2,6-dimethyl-4-aminobenzamide are obtained suchas, for example, N-B-diethylaminoethyl-Z,6-dimethyl-4- aminobenzamideethochloride, N-fi-diethylaminoethyl- 2,6-dimethyl-4-aminobenzamidebenzyl chloride, and the like.

On reacting N B-diethylaminoethyl-Z,6-dimethyl-4- aminobenzamide with asuitable acid such as sulfuric acid, acetic acid, benzoic acid, or thelike, in alcohol, the corresponding acid addition salt ofN-fl-diethylamino-. ethyLZfi-dimethyl- -aminobenzamide is obtained suchas N B-diethylaminoethyl-Z,6-dimethyl-4arninobenzamide sulfate,N-diethylaminoethy"-2,6-dimethyl-4-aminobenzamide acetate, N ,8diethylaminoethyl-2,6-dimethyl-4 aminobennamide benzoate, and the like.

Example 22.-N-/8-DicthylamirtoethyZ-Z-Methyl- 6-Ethyl-4-AminobenzamideFollowing the procedure described in Example 21 except for thesubstitution of N-fi-diethylaminoethyl-Z,6-dimethyl-4-acetamidobenzamide by N-e-diethylaminoethyl-2-methy1-6-ethyl-4-acetamidobenzamide (Example 14),N fi diethylaminoethyl-Z-methyl-6-ethyl-4-aminobenzamide is obtained.

Example 23.-N-,6-DiethylaminoethyZ-Z-Methyl-6-Is0pr0pyl-4-Amin0benzamide Following the procedure described inExample 21 except for the substitution of N-fl-diethylaminoethyl-2,6-dimethyl-4-acetamidobenzamide byN-B-diethylaminoethyl-2-methyl-6-isopropyl-4-acetamidobenzamide (Example15) N-,8-diethylaminoethyl-2-methyl6-isopncpyl-4-aminobenzamide isobtained.

Following the procedure described in Example 21 except for thereplacement of N-e-diethylaminoethyl-2,6-dimethyl-4-acetamidobenzamideby other N-secondary-aminoalkyl-Z,6-dimethyl-4-acetamidobenzamides,other N- s'econdary aminoalkyl-Z,6-dimethyl-4-aminobenzamides, includingtheir acid addition and quaternary ammonium salts, are obtained. Thus,on hydrolyzing N-diethylaminomethyl-Z,6-dimethyl-4-acetamidobenzamide,N-diethylaminomethyl-Z,6-dimethyl-4-aminobenzamide is obtained. In alike manner, N-zeta-diethylaminohexyl-Z,G-dimethyl- 4-aminobenzamide isobtained by hydrolyzingN-zeta-diethylaminohexyl-2,6-dime-thyl-4acetam-idobenzamide; N- 5methylcyclohexylaminoethyl 2,6-dirnethyl-4-aminobenzamide is obtained byhydrolyzing N-B-methyleyclo[hexylaminoethyl-Z,6-dimethyl-4-acetarnidobenzamide; N-methyl-N-B-diethylaminoethyl-2,6-dimethyl-4-aminobenzamide is obtainedby hydrolyzing N-methyl-N-fl-diethylaminoethyl 2,6dimethyl-4-acetamidobenzamide; N-(flmethylcyclohexylaminoethyl) Nethyl-2,6-dimethyl-4- aminobenzamide is obtained by hydrolyzingN-(fi-methylcyclohexylaminoethyl) N ethyl 2,6 dimethyl-4-aetamidobenzamide; N-fi-(l-pyrrolidyl)ethyl-2,6-dirnethyl-4-amiinobenzamide is obtained by hydrolyzing N- -(1-pyrrolidyDethyl-Z,6-dimethyl-4-acetamidobenzamide; N-

ture of hydrogen bromide B (2,2dimethyl-l-pyrrolidyl)ethyl-2,6--dimethyl-4-aminobenzamide is obtainedby hydrolyzing N-fi-(LZ-dimethyl 1 pyrrolidyl)ethyl 2,6dimethyli'acetamidobenza-mide; Nfi-(l-piperidyl)ethyl-2,6-dimethyl-4-aminobenzamide is obtained byhydrolyzing N-fl-(l-piperidyl-ethyl- 2,6 dimethyli-acetamidobenzamide;N-fi-(Z-methyl-b piperidyDethyl 2,6 dimethyll-aminobenzamide is obtainedby hydrolyzing N-fl-(Z-Inethyl-l-piperidyl)ethyl 2,6 dimethyl4-acetamidobenzarnide;N-butyl-N-y-(lpiperidyl)propyl-2,6-dimethyl-4-aminobenzamide is obtainedby hydrolyzing N-butyl-N- y-(I-piperidyl)propyl-2,6-dimethyl-4-aceta-midobenzamide; N-fi-( i-morpholinyl)ethyl-2,6-dimethyl-4-aminobenzamide is obtained by hydrolyzingN-p-(4-morpholinyDethyl-2,6-dimethyl-4-acetamidobenzamide;N-{i-(Z-methyl-4-morpholinyl)ethyl-2,6- dimethyli-aminobenzarnidc isobtained by hydrolyziug N43-(2-methyl-4-morpholinyl)ethyl 2,6dimethyli-acetamidobenzamide; andN-p-methylethylaminoethyl-L6-dimethyli-aminobenzamide is obtained byhydrolyzing N- 13methylethylaminoethyl-2,6-dirnethyl-4-acetamidobenzamide.

Following the procedure described in Example 21 except for thesubstitution of N- 8-diethylamin0ethyl-2,6-dimethyl-4-acetamidobenzamide by other hindered 4- acylamidobenzamides,the following hindered 4-aminobenzamides, including their acid additionand quaternary ammonium salts, are obtained:

N-fi-diethylaminoethyl-Z-methyl-4saminobenzamide,N-fi-diethylaminoethyl-Zethyl-3,6-dimethyl-4-aminobenzamide,N-fl-diethylaminoethyl-Z,6-diethyl-4-aminobenzamide, N-B-diethylaminoethyl-2-methyl-6- Z-furyl) -4-amin oibenzamide,N-fi-diethylaminoethyl-Z-methyl-6-p-meth-oxyphenethyl-4-aminobenzamide,N-BniethyIaminOethyI-Z,6-diphenyl-4 aminobenzamide,N-B-diethylaminoethyl-2-methyl-6-cyclohexyli-amino- 'benzamide,N-fl'diethylaminoethyl-2-methyl-3-p-methoxypenethyltaminobenzamide,N-fi-diethylaminoethyl-Z-methyl-6-n-hexyl-4-arninobenzamide,N-fi-diethylaminoethyl-Z-methyl-6-isopropyl-4-aminobenzamide,N-fl-diethylaminoethyl-2-methyl-6-p-methoxyphenethyl- 4-aminobenzamide,N-fi-diethylaminoethyl-2,6-diethyl4-aminobenzamide,N-fi-diethylaminoethyl-Z'methyl-6-o-methyibenzyl-4- aminobenzamide,N-B-diethylaminoethyl-2-methyl-6-benzyl-4-aminobenzamide,N-B-diethylaminoethyl-Z-ethyl-4-aminobenza1nide,N-p-d-iethylaminoethyl-Z-n-butyl-4-aminobenzamide,N-f3diethy1aminoethyl2-rnethyl-6-p-tolyl-4 aminobenzamide,N-ft-diethylaminoethyl-Z-methyl-3 (3 ,7 -dimethyloctyl)4-aminobenzamide, N-B-diethylaminoethyl-Z,3-dimethy1-4-aminobenzamide,N-B-diethylaminoethyl-2-methyl-3-m-methoxyphenethyl- 4-aminobenzamide,N-[S-diethylaminoethyl-2,6-dirnethyl-3-ethyl-4-aminobenzamide,N-B-diethylaminoethyl-Z-methyl-3 -benzyl-6 isopropyl-4- aminooenzamide,and the like.

Where arylsulfonyl halides, aroyl halides, and the like, have been usedas 'acylating agents to form the aforementioned NB-diethylaminoethyl-Z,fi-dimethyll-p toiuenesulfonamidobenzamide, NB-diethylaminoethyl-2,6-dimethyl-4-benzenesulfonamidobenzamide,N-e-diethylaminoethyl 2,6-dimethyl-4-benzamidobenzamide, and the like,these compounds are hydrolyzed to the corresponding hindered4-aminobenzarnide by reaction with a mixand phenol in an acetic acidmedium, in the manner set forth in U. S. Patent 2,5 62,222.

The novel hindered 4-aminobenzamides of the invention, their acidaddition and quaternary ammonium salts, are characterized bypharmacological activity, and more specifically, local anestheticactivity.

Example .24.--,B-Diethyiaminoethyl 2,6-Dimethyl- 4-Aminobenz0ate In a500-milliliter, one-neck flask fitted with a reflux condenser are placed26 grams (0.085 mole) of fl-diethylarninoethyl2,6-dimethyl-4-acetamidobenzoate (Example 16), 22 grams of sodiumhydroxide, fifty milliliters of water and 200 milliliters of ethylalcohol. The mixture is refluxed for four hours at a temperature ofdegrees centigrade and then 200 milliliters of solvent is removed bydistillation. The residue is cooled to twenty degrees centigr-ade, 300milliliters of water added thereto and the resulting solution isextracted with ether. The ether extract is filtered, dried and thendistilled. There is obtained a light brown oil, identified by infraredanalysis as B-diethylaminoethyl 2,6-dimet'hyl-4- aminobenzoate boilingbetween 155 and 157 degrees centigrade at a pressure of 0.04 millimeterof mercury and possessing an index of refraction n =l.5477.

AnaIysis.--Calculated for C15H24N2o2: N, 10.60. Found: N, 10.49.

By heating a benzene solution of [i-diethylaminoethyl2,6-dimethyl-4-aminobenzoate and methyl bromide and cooling andconcentrating the resulting solution, fl-diethylaminoethyl2,6-dimethyl-4-am-inobenzoate methobromide is obtained.

Similarly, by reacting fl-diethylaminoethyl 2,6-dimethyl-4-aminobenzoatewith other esters such as, for example, ethyl chloride, benzyl chloride,and the like, the corresponding quaternary ammonium salts offi-diethylaminoethyl 2,6-dimethyl-4-aminobenzoate are obtained such as,for example, fl-diethylaminoethyl 2,6-dimethyl- 4-aminobenzoateethochloride, B-diethylaminoethyl 2,6- dimethyl-4-aminobenzoate benzylchloride, and the like.

Example 25.--,8-Diethylaminoethyl 2,6-Dimethyl- 4-Amin0benz0ateMonohydrochloride One gram of fi-diethyl aminoethyl2,6-dimethyl-4-aminobenzoate (Example 24) is dissolved in thirtymilliliters of diethyl ether and gaseous hydrogen chloride is bubbledinto the solution until the precipitation of white solid ceases. Thesolid material is collected by filtration, immediately dissolved inisopropanol and then recrystallized therefrom. fi-Diethylaminoethyl2,6-dimethyl-4-aminobenzoate monohydrochloride is thus obtained meltingbetween 129 and degrees centigrade.

Analysis-Calculated for C H ClN O Found: Ci, 11.67.

Example 26.-B-Diethylaminoethyl 2,6-Dimethyl-4- AminobenzoateDilzydrochloride One gram of B-diethylaminoethyl2,6-dimethyl-4-aminobenzoate (Example 24) is dissolved in thirtymilliliters of diethyl ether and gaseous hydrogen chloride is bubbledinto the solution until the precipitation of white solid ceases. Thesolid material is collected by filtration and exposed to the air. Over aperiod of eight hours, the white solid material becomes gummy, light tanin color and then resolidifies. Upon recrystallization from isopropanol,white crystalline e-diethylaminoethyl 2,6-dimethyl- 4-amin0benzoatedihydrochloride is obtained melting between 194 and 194.5 degreescentrigrade.

Analysis.--Calc. for C H Cl N O 8.32. Found: C1, 20.61; N, 8.28.

Example 2 7.-fi-Diethylamin0ethyl 2,6-Dimethyl-4- Aminobenzoate CitrateCl, 21.07; N,

Following the procedure set forth in Example 25 except for thereplacement of hydrogen chloride by citric acid, fi-diethylaminoethyl2,6-di1nethyl-4-aminobenzoatecitrate is obtained in the form ofcolorless crystals.

25 Example 28.fi-]-Piperidylethyl 2,6-Dimethyl-4- AminobenzoateFollowing the procedure described in Example 24 except for thesubstitution of 8-diethylarninoethyl 2,6-din1ethyl-4-acet-amidobenzoateby 8-1-piperidylethyl 2,6- dimethyl-4-acetamidobenzoate (Example 18),there is obtained a forty percent yield of p-l-piperidylethyl 2,6dimethyl-4-aminobenzoate boiling between 175 and 180 degrees centigradeat a pressure of 0.03 millimeter of mercury.

Example 29.-{3-1 -Piperidylethyl 2,6-Dimetlzyl-4- AminobenzoateDihydrochloride Following the procedure described in Example 26 exceptfor the substitution of ,B-diethylaminoethyl2,6-dimetl1yl-4-aminobenzoate by p 1 piperidylethyl2,6-dimethyl-4-aminobenzoate (Example 28), there is obtainedj3-l-piperidylethyl 2,6-dimethyl-4-aminobenzoate dihydrochloride meltingbetween 223 and 225 degrees centigrade (tube).

Analysis-Cflc. for C H Cl N O C, 55.01; H, 7.50; N, 8.02; Cl, 20.21.Found: C, 55235; H, 7.64; N, 8.19; Cl, 19.83.

Example 30.-;8-4-M0rpholinylethyl 2,6-Dimethyl-4- AminobenzoaleFollowing the procedure described in Example 24 except for thesubstitution of fi-diethylaminoethyl 2,6-dimethyl-4-acetarnidobenzoateby ,B-4-morpholinylethyl 2,6- dimethyl-4-acetamidobenzoate (Example 17),,B-4-n1orpholinylethyl 2,6-dimethyl-4-aminobenzoate is obtained.

Example 31 .-j3-Diethylaminoethyl 2-Methyl-6- Ethyl-4A min b erzzoareFollowing the procedure described in Example 24 except for thereplacement of ,G-diethylaminoethyl 2,6-dimethyl---acetam-idobenzoate by[i-diethylaminoethyl 2- methyl-6-ethyl-4-acetamidobenzoate (Example 19),f3- diethylaminoethyl 2-methyl-6-ethyl-4-aminobenzoate is obtained.

Example 32.-B-Diethylaminoelhyl 2-Methyl-6- Is0pr0pyl-4-AminobenzoateFollowing the procedure described in Example 24 except for thesubstitution of ,B-diethylaminoethyl 2,6-dimethyl-4-acetamidobenzoate byfl-diethylaminoethyl 2- rnethyl-6-isopropyl-4-acetamidobenzoate (Example20), ,8 diethylaminoethyl 2 methyl-6-isopropyl-4-aminobenzoate isobtained.

In the same manner, hindered 4-acylamidobenzoic acid esters arehydrolyzed by the procedure described in Example 24- to form thecorresponding hindered 4-aminobenzoic acid esters. Thus,zeta-diethylaminohexyl 2,6- dimethyl-4-aminobenzoate is obtained by thehydrolysis of zeta-diethylaminohexyl 2,6-dimethyl-4-acetamidobenzoate;,8 methylethylaminoethyl 2,6 dimethyl-4-aminobenzoate is obtained by thehydrolysis of B-methylethylaminoethy-l2,6-=dimethyl-4-acetamido-ber1oate; B-dicyclohexylaminoethyl 2,6dimethyl 4-aminobenzoate is obtained by the hydrolysis of{3-dicyclohexylaminoethyl 2,6- dimethyl 4 acetamidobenzoate;,B-I-pyrrolidylethyl 2,6- dimethyl-4-aminobenzoate is obtained by thehydrolysis of fi-l-pyrrolidylethyl 2,6-dimethyl-4-acetamidobenzoate.

Similarly, the following hindered 4-ann'nobenzoic acid esters areobtained by hydrolysis of the corresponding hindered 4-acylamidobenzoicacid esters:

fi-Ethylbenzylaminoethyl 2,6-dimethyl-4-aminobenzoate,

B-Dibenzylarninoethyl 2,6-Dimethyl-4-aminobenzoate,

fi-(Z-methyl-l-pyrrolidyl)ethyl 2,6-dimethyl-4-aminobenzoate,

S-(Z-methyl-l-piperidyl)ethyl 2,6 dimethyl-4-aminobenzoate,

fl-(2-methyl-4-morpholinyl)ethyl 2,6 dimethyl-4-aminobenzoate,

26 V fl-Dirnethylaminoethyl 2-methyl-4-aminobenzoate,fl-Diethylaminoethyl 2-ethyl-3,6-dimethyl-4-aminobenzoate,

fi-Diethylaminoethyl 2, 6 diethyl-4-aminobenzoate,

B-Diethylaminoethyl 2-methyl-6-(2-furyl)-,4- aminobenzo ate,

fl-Diethylaminoethyl 2 methyl-6-p-methoxyphenethyl-4- aminobenzoate,

fl-Diethylaminoethyl 2,6-diphenyl-4-a1ninobenz0ate,

,B-Diethylaminoethyl 2 methyl-6-cyclohexyl 4aaminobenzoate,

fi-Diethylaminoethyl 2 methyl-3-p-methoxyphenethyl-4- aminobenzoate,

BDiethylaminoethyl 2-methyl-6-n-hexyl-4-aminobenzoate,

;8-Dimethylaminopropyl 2-metl1yl-6-n-propyl-4-aminobenzoate,

,B-Dimethylaminoisopropyl 2-methyl-6-n-propyl-4-aininobenzoate,

v-Dimethylaminopropyl 2-methyl-6-n-propyl-4-aminobenzoate,

B-Diethylaminoethyl Z-methyl-6-o-methylbenzyl-4-aminobenzoate,

[3Diethylaminoethyl 2methyl-6-benzyl-4-annnobenzoate,

l3-Diethylarrdnoethyl 2-ethyl-4-aminobenzoate,

fi-Diethylaminoethyl 2-n-buty-l-4-aminobenzoate,

fi-Diethylaminoethyl Z-methyl-6-p-ttolyl-4-aminobenzoate,

fi-Diethylaminoethyl 2 methyl-3-(3,7-Dimethylootyl) -4- aminobenzoate,

fl-Diethylaminoethyl 2,3-dimethyl-4-aminobenzoate,

fl-Diethylaminoethyl 2 methyl-3-m-methoxyphenethyl-4- aminobenzoate,

18-Diethylarninoethyl 2,6-dimethyl-3-ethyl-4-aminobenzoate,

fi-Diethylaminoethyl 2 methyl 3 benzyl-6-isopropyl-4- aminobenzo ate,and the like.

Where arylsulfonyl halides, aroyl halides, and the like, have been usedas acylating agents to form the aforementioned fi-diethylaminoethyl2,6-dimethyl-4- -toluenesulfonamidobenzoate, fi-diethylaminoethyl2,6-dimethyl- 4-benzenesulfonamidobenzoate, fi-diethylaminoethyl 2,6-dirnethyl-4-benzamidobenzoate, and the like, these compounds arehydrolyzed to the corresponding hindered 4-aminobenzoic acid esters byreaction with a mixture of hydrogen bromide and phenol in an acetic acidmedium, in the manner set forth in U.S. Patent 2,562,222.

Similarly, by the procedure set forth in Examples 24 to 27, the acidaddition and quaternary ammonium salts of hindered 4-aminobenzoic acidesters are likewise obtained.

The novel hindered 4-aminobenzoic acid esters, their acid addition andquaternary ammonium salts, are characterized by pharmacologicalactivity, and more specifically, local anesthetic activity.

Following the procedure described in Example 24, hindered4-acylainidothiolobenzoic acid esters are hydrolyzed to thecorresponding hindered 4-arninothiolobenzoic acid esters. Thus, forexample, ,8-diethylaminoethyl 2,6-dimethyl-4-acetamidothiolobenzoate ishydrolyzed to fl-diethylaminoethyl 2,6-dimethyl-4-aminothiolobenzoate.In a like manner, zeta-diethylaminohexyl 2,6-dimethyl-4-aminothiolobenzoate is obtained by the hydrolysis ofZeta-diethylaminohexyl 2,6-dimethyl-4-acetamidothiolobenzoate;fi-methylethylaminoethyl 2,6 -dimethyl-4-aminothiolobenzoate is obtainedby the hydrolysis of fi-methylethylaminoethyl2,6-dhnethyl-4-acetamidothiolobenzoate; ,B-dicyclohexylaminoethyl2,6-dimethyl-4- aminothiolobenzoate is obtained by the hydrolysis of f2dicyclohexylaminoethyl 2,6-dimethyl-4-acetamidothiolobenzoate;,B-I-pyrrolidylethyl 2,6-dimethyl-4-aminothiolobenzoate is obtained bythe hydrolysis of fi-l-pyrrolidylethyl2,6-dimethyl-4-acetamidothiolobenzoate, fl-l-piperidylethyl2,6-dimethyl-4-aminothiolobenzoate is obtained by the hydrolysis ofp-l-piperidylethyl 2,6-dimethyl-4- acetamidothiolobenzoate; and,8-4-morpholinylethyl 2,6-

2'7 dimethyll-aminothiolobenzoate is obtained by the hydrolysis offi-4-morpholinylethyl 2,6-dimethyl-4-accta midothiolobenzoate.

By the same procedure, the following hindered 4-aminothiolobenzoic acidesters are obtained from the corresponding hindered4-acylamidothiolobenzoic acid esters:

'fl-Bthylbenzylaminoethyl 2,6-dirnethyl-4-aminothio1obenzoate,

fl-Dibenzylaminoethyl 2,6-dimefl1yl-4-aminothiolobenzoate,

6- (2-methyl-l-pyrrolidyl) ethyl 2,6-dimethyl-4-aminothiolobenzoate,

18- (2-methyl-l -piperidyl ethyl 2,6-climethyl-4-arninothiolobenzoate,

fl-(2-methyl-4-morpholinyl) ethyl 2,6-dimethyl-4-aminothiolobenzoate,

,B-Diethylaminoethyl 2-methyl-4-aminothiolobenzoate,

,B-Diethylaminoethyl 2-ethyl-3,6-dimethyl-4-aminothiolobenzoate,

fi-Diethylaminoethyl 2-methyl-6-(2-furyl) -4-aminothiolobenzoate,

fi-Diethylaminoethyl Z-methyl-6p-methoxyphenethy1-4-aminothiolobenzoate,

fi-Diethylaminoethyl 2-methyl-6-cyclohexyl-4-aminothiolobenzoate,

,B-Diethylaminoethyl Z-methyl-3-p-methoxyphenethyl-4-aminothiolobenzoate,

fl-Diethylaminoethyl Z-methyl-6-n-hexyl-4-aminothiolobenzoate,

fi-Diethylaminoethyl Z-methyl-6-isopropyl-4-aminothiolobenzoate,

p-Diethylaminoethyl Z-methyl-6-o-methylbenzyl-4-aminothiolobenzoate,

B'DiethylaminOethyl Z-methyl-6-benzyl-4-aminothiolobenzoate,

fl-Diethylaminoethyl 2-ethyl-4-aminothiolobenzoate,

B-Diethylaminoethyl Z-n-butyl-4-aminothiolobenzoate,

fi-Diethylaminoethyl 2-methyl-6-p-tolyl4-aminothiolobenzoate,

e-Diethyl'aminoethyl 2-methyl-3 (3 ,7-dimethyloctyl) -4-aminothiolobenzoate,

B-Diethylaminoethyl 2,3-dimethyl-4-aminothiolobenzoate,

fi-Diethylaminoethyl 2-methyl-3-m-methoxyphenethyl-4-aminothiolobenzoate,

B-Diethylaminoethyl 2,6-din-rethyl-S-ethyl-4-aminothiolobenzoate,

fi-Diethylaminoethyl 2-methyl-3-benzyl-6-isopropyl-4-aminothiolobenzoate, and the like.

Similarly, by the procedure set forth in Examples 24 to 27, the acidaddition and quaternary ammonium salts of hindered 4-aminothiolobenzoicacid esters are likewise obtained.

Where arylsulfonyl halides, arolyl halides, and the like, have been usedas acylating agents to form the aforementioned B-diethylaminoethyl2,6-dirnethyl-4-p-toluenesnlfonamidothiolobenzoate, fi-diethylaminoethyl2,6-dimethyl-4-benzenesulfonarnidothiolobenzoate, B-diethylaminoethyl2,6-dimethyll-benzamidothiolobenzoate, and the like, these compounds arehydrolyzed to the corresponding hindered 4-aminothiolobenzoic acidesters by reaction with a mixture of hydrogen bromide and phenol in anacetic acid medium in the manner set forth in US. Patent 2,562,222.

The novel hindered a-aminothiolobenzoic acid esters,

.their acid addition and quaternary ammonium salts, are characterized bypharmacological activity, and more specifically,'local anestheticactivity.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and describedherein, as obvious modifications and equivalents will be apparent to oneskilled in the art. The invention is therefore to be limited only by thescope of the appended claims,

I claim: l. A process for preparing compounds of the formula:

i R;- 2- R1 wherein n is an integer from one to six inclusive, R is asecondary-amino radical, R is a member selected from the groupconsisting of hydrogen and alkyl, cycloalkyl, aralkyl, aryl' andheterocyclic radicals; R is a member selected from the group consistingof alkyl and aryl radicals; R is a member selected from the groupconsisting of hydrogen and alkyl and aralkyl radicals; and Y is a memberselected from the group consisting of oxygen, sulfur, imino, andalkylirnino; which comprises subjecting a hindered4-oXo-2-cyclohexene-l-carboxylic acid ester of the formula:

wherein R is a member selected from the group consisting of alkyl andaralkyl radicals, and R R and R are as defined above, to oximation,aromatizing and acylating the resulting hindered4-oximino-2-cyclohexene-l-carboxyh'c acid ester, hy-drolyzing thehindered 4-acylamidobenzoic acid ester thus obtained followed byacylation to form a hindered 4-acylamidobenzoic acid, reacting said acidwith an inorganic acid halide, reacting the hindered 4-acylamidobenzoylhalide thus obtained with a compound of the formula:

wherein Y, R and n are as defined above, and then hydrolyzing thecompound thus obtained.

2. A process for preparing compounds of the formula.

0: -YCnHmR wherein R is an acyl group, and n, R, R R R and Y are asdefined in claim 1, which comprises subjecting a hindered4-oXo-2-cyclohexene-l-carboxylic acid ester of the formula:

O=(EO R5 wherein R R R and R are as defined in claim 1, to oximation,aromatizing and acylating the resulting hindered4-oximino-2-cyc1ohexene-lcarboxylic acid ester, hydrolyzing the hindered4-acylamidobenzoic acid ester thus obtained following by acylation toform a hindered 4-acylamidobenzoic acid, reacting said acid with aninorganic acid halide and then reacting the hindered 4-acylamidobenzoylhalide thus obtained with a compound of the formula:

HYCnH nR wherein Y, R and n are as defined in claim 1.

(References on following page) References Cited in the file of thispatent UNZTED STATES PATENTS OTHER REFERENCES Grob: Helvetica ChhnicaActa, volume 33, pages 39 1787-96, abstracted in Chem. Abstracts, volume45, column 3804(f), 1950.

Rhodehamel: I our. of the American Chem. Soc., volume 73, page 5902,abstracted in Chem. Abstracts, Volume 46, column 11181(b) (1951).

Dvoretsky et a1.: I our. of Org. Chem, volume 18, pages 615-19, June 16,1952.

Tetracaine: Merck Index, Sixth Edition, p. 939 (1952).

1. A PROCESS FOR PREPARING COMPOUNDS OF THE FORMULA: